rs104893919

Positions:

• chr5-149978184-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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 (★★). 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:23 O:1
• Conservation: PhyloP100: 1.35

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-149978184-C-T is Pathogenic according to our data. Variant chr5-149978184-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149978184-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A2	NM_000112.4	c.532C>T	p.Arg178*	stop_gained	2/3	ENST00000286298.5	NP_000103.2
SLC26A2	XM_017009191.3	c.532C>T	p.Arg178*	stop_gained	2/4		XP_016864680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A2	ENST00000286298.5	c.532C>T	p.Arg178*	stop_gained	2/3	1	NM_000112.4	ENSP00000286298.4
SLC26A2	ENST00000503336.1	c.205C>T	p.Arg69*	stop_gained	1/2	3		ENSP00000426053.1
SLC26A2	ENST00000690410.1	n.764C>T		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152040 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251008 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135654

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 SAS exome AF: 0.0000327

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.: 0 Cov.: 33 AF XY: 0.0000950 AC XY: 69 AN XY: 726340

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74260

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000129 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2024	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) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Achondrogenesis, type IB Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 15, 2008	- -
Pathogenic, criteria provided, single submitter	research	Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 11, 2019	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.‚Äã -

Atelosteogenesis type II Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	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. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 19, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Nov 17, 2021	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. -

Diastrophic dysplasia Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 15, 2008	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 11, 2019	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.‚Äã -

SLC26A2-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 19, 2018	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; Macías-Gómez 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. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 11, 2024	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. -

Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 05, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	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

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Dec 11, 2019

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.‚Äã -

Sulfate transporter-related osteochondrodysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 02, 2017

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

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Dec 11, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.86
GERP RS		5.4

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

LitVar

Other links and lift over

dbSNP: rs104893919; hg19: chr5-149357747; COSMIC: COSV105841713; COSMIC: COSV105841713;