NM_000112.4:c.532C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000112.4(SLC26A2):c.532C>T(p.Arg178*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000967 in 1,612,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R178R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

SLC26A2
NM_000112.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:24O:1

Conservation

PhyloP100: 1.35

Publications

20 publications found

Variant links:

Genes affected

SLC26A2 (HGNC:10994): (solute carrier family 26 member 2) The diastrophic dysplasia sulfate transporter is a transmembrane glycoprotein implicated in the pathogenesis of several human chondrodysplasias. It apparently is critical in cartilage for sulfation of proteoglycans and matrix organization. [provided by RefSeq, Jul 2008]

SLC26A2 Gene-Disease associations (from GenCC):

achondrogenesis type IB
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, ClinGen
atelosteogenesis type II
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics
diastrophic dysplasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
multiple epiphyseal dysplasia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
multiple epiphyseal dysplasia type 4
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P

SLC26A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 5-149978184-C-T is Pathogenic according to our data. Variant chr5-149978184-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 4092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A2	NM_000112.4 link	c.532C>T	p.Arg178*	stop_gained	Exon 2 of 3	ENST00000286298.5	NP_000103.2	P50443
SLC26A2	XM_017009191.3 link	c.532C>T	p.Arg178*	stop_gained	Exon 2 of 4		XP_016864680.1	P50443

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC26A2	ENST00000286298.5 link	c.532C>T	p.Arg178*	stop_gained	Exon 2 of 3	1	NM_000112.4	ENSP00000286298.4	P50443
SLC26A2	ENST00000503336.1 link	c.205C>T	p.Arg69*	stop_gained	Exon 1 of 2	3		ENSP00000426053.1	H0YA38
SLC26A2	ENST00000690410.1 link	n.764C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000131

AC:

AN:

251008

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000952

AC:

139

AN:

1460582

Hom.:

Cov.:

AF XY:

0.0000950

AC XY:

AN XY:

726340

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33470

American (AMR)

AF:

0.000268

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000103

AC:

114

AN:

1110896

Other (OTH)

AF:

0.000133

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000112

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41374

American (AMR)

AF:

0.000197

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000124

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 10, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Common pathogenic variant associated with SLC26A2-related chondrodysplasias, typically associated with a severe phenotype when in trans with a second loss-of-function variant (PMID: 21155763, 11241838); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26990548, 11241838, 8528239, 18925670, 15294877, 11448940, 31589614, 31345219, 35587316, 36007841, 32333414, 21155763, 15316973) -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 14, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 17, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Achondrogenesis, type IB

Pathogenic:5

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 15, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 11, 2019

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000112.3(SLC26A2):c.532C>T(R178*) is classified as pathogenic in the context of SLC26A2-related disorders and is associated with Achondrogenesis Type 1B. Sources cited for classification include the following: PMID 11448940, 21155763 and 8528239. Classification of NM_000112.3(SLC26A2):c.532C>T(R178*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.â€šÃ„Ã¶âˆšÃ‘âˆšÂ£ -

Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 28, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Atelosteogenesis type II

Pathogenic:3

Feb 19, 2016

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Nov 17, 2021

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This heterozygous stop gain variant has been previously reported by Macías-Gómez NM et al in 2004 in a Mexican patient. In our study this variant is present in compound heterozygous state with another mis-sense variant-c.1382C>T (p.A461V). The allele frequency-0.0131% in gnomAD (Aggregated) database and not reported in 1000g till date. Phenotype observed in the proband was severe shortening of all long bones, exaggerated lumbar lordosis, big toe and radial shortening. Atelosteogenesis II is an autosomal recessive disorder and can be caused by homozygous or compound heterozygous mutations. Based on phenotypic observation and available literature, we classify this variant as pathogenic. -

Jan 05, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.532C>T;p.(Arg178*) variant creates a premature translational stop signal in the SLC26A2 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 4092; PMID: 20301524; 21155763; 18925670; 15316973; 11241838) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11448940; 15294877) - PS3_moderate. The variant is present at low allele frequencies population databases (rs104893919 – gnomAD 0.01118%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg178*) was detected in trans with a pathogenic variant (PMID: 21155763; 18925670; 15316973) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic. -

Diastrophic dysplasia

Pathogenic:2Other:1

Nov 15, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 11, 2019

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

SLC26A2-related disorder

Pathogenic:2

Mar 11, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SLC26A2 c.532C>T variant is predicted to result in premature protein termination (p.Arg178*). This variant is one of the most common pathogenic changes in the SLC26A2 gene, and has been documented in multiple affected individuals (Barbosa et al. 2011. PubMed ID: 21155763; https://www.ncbi.nlm.nih.gov/books/NBK1350/). When detected in the compound heterozygous or homozygous states, it is reported in patients with severe SLC26A2 associated phenotypes of achondrogenesis type IB, diastrophic dysplasia, and atelosteogenesis type 2 (Superti-Furga et al.1996. PubMed ID: 8528239; Panzer et al. 2008. PubMed ID: 18925670). Functional studies support the pathogenicity of this change (Karniski. 2001. PubMed ID: 11448940). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Oct 19, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC26A2 c.532C>T (p.Arg178Ter) variant is a stop-gained variant. Across a selection of literature, the p.Arg178Ter variant has been reported in a compound heterozygous state in at least 13 probands (Superti-Furga 1996; MacÃas-GÃ³mez et al. 2004; Panzer et al. 2008; Barbosa et al. 2011; Mattos et al. 2014). In at least one family an unaffected father was heterozygous for this variant. The p.Arg178Ter variant was absent from at least 200 controls, but is reported at a frequency of 0.00029 in the Latino population from the Genome Aggregation Database. In Xenopus oocytes, the p.Arg178Ter variant was shown to have significantly reduced (<10%) sulfate transport compared to wildtype, and similar findings were noted in HEK-293 cells (Karniski et al. 2001; Karniski et al. 2004). Based on the collective evidence, the p.Arg178Ter variant is classified as pathogenic for SLC26A2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II

Pathogenic:2

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg178*) in the SLC26A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC26A2 are known to be pathogenic (PMID: 7923357, 10482955, 11241838). This variant is present in population databases (rs104893919, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with SLC26A2-related disease (PMID: 8528239, 15316973, 18925670, 21155763). ClinVar contains an entry for this variant (Variation ID: 4092). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Multiple epiphyseal dysplasia type 4

Pathogenic:1

Dec 11, 2019

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sulfate transporter-related osteochondrodysplasia

Pathogenic:1

Feb 02, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The SLC26A2 c.532C>T (p.Arg178X) variant results in a premature termination codon, predicted to cause a truncated or absent SLC26A2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.1724delA). One in silico tool predicts a damaging outcome for this variant, which has been confirmed by at least one functional study (Karniski_2004). This variant was found in 13/120994 control chromosomes at a frequency of 0.0001074, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC26A2 variant (0.002958). This variant has been reported in multiple STRO patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

3MC syndrome 2

Pathogenic:1

Dec 11, 2019

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

PhyloP100

1.4

Vest4

0.86

GERP RS

5.4

PromoterAI

-0.030

Neutral

(source)

Mutation Taster

=8/192

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over