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rs104893919

chr5-149978184-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000112.4(SLC26A2):c.532C>T(p.Arg178Ter) 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

4
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 1.35
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
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 UniProt
SLC26A2NM_000112.4 linkuse as main transcriptc.532C>T p.Arg178Ter stop_gained 2/3 ENST00000286298.5
SLC26A2XM_017009191.3 linkuse as main transcriptc.532C>T p.Arg178Ter stop_gained 2/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC26A2ENST00000286298.5 linkuse as main transcriptc.532C>T p.Arg178Ter stop_gained 2/31 NM_000112.4 P1
SLC26A2ENST00000503336.1 linkuse as main transcriptc.205C>T p.Arg69Ter stop_gained 1/23
SLC26A2ENST00000690410.1 linkuse as main transcriptn.764C>T non_coding_transcript_exon_variant 2/2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000112
AC:
17
AN:
152040
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.000131
AC:
33
AN:
251008
Hom.:
0
AF XY:
0.000133
AC XY:
18
AN XY:
135654
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 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
show subpopulations
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
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000112
AC:
17
AN:
152040
Hom.:
0
Cov.:
32
AF XY:
0.0000943
AC XY:
7
AN XY:
74260
show subpopulations
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
?
    Exome Aggregation Consortium database
AF:
0.000107
AC:
13
EpiCase
AF:
0.000218
EpiControl
AF:
0.000237

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:21Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 14, 2014- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJan 17, 2022- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 13, 2023Nonsense 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; Common pathogenic variant associated with SLC26A2-related chondrodysplasias, typically associated with a severe phenotype when in trans with a second loss-of-function variant (Rossi et al., 2001; Barbosa et al., 2011); This variant is associated with the following publications: (PMID: 26990548, 11241838, 8528239, 18925670, 15316973, 15294877, 11448940, 31589614, 31345219, 35587316, 36007841, 21155763, 32333414) -
Likely pathogenic, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Achondrogenesis, type IB Pathogenic:5
Pathogenic, criteria provided, single submitterresearchDiagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS-- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 15, 2008- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 11, 2019NM_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 -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsSep 28, 2023- -
Atelosteogenesis type II Pathogenic:3
Pathogenic, no assertion criteria providedclinical testingInstitute of Medical Genetics and Genomics, Sir Ganga Ram HospitalNov 17, 2021This 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. -
Pathogenic, no assertion criteria providedclinical testingCounsylFeb 19, 2016- -
Pathogenic, criteria provided, single submitterclinical testingDASAJan 05, 2022The 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
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 15, 2008- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 11, 2019NM_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:1
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaOct 19, 2018The 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. -
Multiple epiphyseal dysplasia type 4 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 11, 2019NM_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 -
Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 25, 2024This 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. -
Sulfate transporter-related osteochondrodysplasia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 02, 2017Variant 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 submitterclinical testingMyriad Genetics, Inc.Dec 11, 2019NM_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
MutationTaster
Benign
1.0
A
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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