rs78676079

Positions:

chr5-149981067-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000112.4(SLC26A2):c.1474C>T(p.Arg492Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,614,088 control chromosomes in the GnomAD database, including 428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 26 hom., cov: 32)

Exomes 𝑓: 0.021 ( 402 hom. )

Consequence

SLC26A2
NM_000112.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19O:1

Conservation

PhyloP100: 1.51

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01479131).

BP6

Variant 5-149981067-C-T is Benign according to our data. Variant chr5-149981067-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 65559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149981067-C-T is described in Lovd as [Likely_pathogenic]. Variant chr5-149981067-C-T is described in Lovd as [Benign]. Variant chr5-149981067-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0158 (2405/152270) while in subpopulation NFE AF= 0.025 (1701/68014). AF 95% confidence interval is 0.024. There are 26 homozygotes in gnomad4. There are 1134 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A2	NM_000112.4 linkuse as main transcript	c.1474C>T	p.Arg492Trp	missense_variant	3/3	ENST00000286298.5	NP_000103.2	P50443
SLC26A2	XM_017009191.3 linkuse as main transcript	c.1474C>T	p.Arg492Trp	missense_variant	3/4		XP_016864680.1	P50443

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A2	ENST00000286298.5 linkuse as main transcript	c.1474C>T	p.Arg492Trp	missense_variant	3/3	1	NM_000112.4	ENSP00000286298.4		P50443
SLC26A2	ENST00000503336.1 linkuse as main transcript	c.372+2716C>T		intron_variant		3		ENSP00000426053.1		H0YA38

Frequencies

GnomAD3 genomes

AF:

0.0158

AC:

2405

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00391

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.000961

Gnomad SAS

AF:

0.00664

Gnomad FIN

AF:

0.0199

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.0250

Gnomad OTH

AF:

0.0173

GnomAD3 exomes

AF:

0.0167

AC:

4201

AN:

251248

Hom.:

AF XY:

0.0168

AC XY:

2282

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00344

Gnomad AMR exome

AF:

0.0104

Gnomad ASJ exome

AF:

0.0214

Gnomad EAS exome

AF:

0.000979

Gnomad SAS exome

AF:

0.00670

Gnomad FIN exome

AF:

0.0201

Gnomad NFE exome

AF:

0.0246

Gnomad OTH exome

AF:

0.0186

GnomAD4 exome

AF:

0.0212

AC:

31038

AN:

1461818

Hom.:

402

Cov.:

AF XY:

0.0211

AC XY:

15365

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00385

Gnomad4 AMR exome

AF:

0.0102

Gnomad4 ASJ exome

AF:

0.0225

Gnomad4 EAS exome

AF:

0.000605

Gnomad4 SAS exome

AF:

0.00766

Gnomad4 FIN exome

AF:

0.0209

Gnomad4 NFE exome

AF:

0.0241

Gnomad4 OTH exome

AF:

0.0183

GnomAD4 genome

AF:

0.0158

AC:

2405

AN:

152270

Hom.:

Cov.:

AF XY:

0.0152

AC XY:

1134

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00390

Gnomad4 AMR

AF:

0.0103

Gnomad4 ASJ

AF:

0.0228

Gnomad4 EAS

AF:

0.000963

Gnomad4 SAS

AF:

0.00664

Gnomad4 FIN

AF:

0.0199

Gnomad4 NFE

AF:

0.0250

Gnomad4 OTH

AF:

0.0171

Alfa

AF:

0.0218

Hom.:

Bravo

AF:

0.0141

TwinsUK

AF:

0.0251

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0217

AC:

187

ExAC

AF:

0.0169

AC:

2052

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0241

EpiControl

AF:

0.0216

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SLC26A2: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Diastrophic dysplasia

Benign:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The p.Arg492Trp variant in SLC26A2 has been reported in at least 2 individuals with diastrophic dysplasia (PMID: 11241838), but has also been identified in >2% of European (non-Finnish) chromosomes and 21 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive diastrophic dysplasia. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Multiple epiphyseal dysplasia type 4

Benign:2

Likely benign, criteria provided, single submitter	literature only	Counsyl	Apr 10, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Achondrogenesis, type IB

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Atelosteogenesis type II

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sulfate transporter-related osteochondrodysplasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.24

MPC

0.33

ClinPred

0.024

GERP RS

6.2

Varity_R

0.80

gMVP

0.85

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over