rs78676079

chr5-149981067-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Synonymous variant affecting the same amino acid position (i.e. R492R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (26 hom., cov: 32)
  • Exomes 𝑓: 0.021 (402 hom.)
• Consequence: SLC26A2 NM_000112.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 1.51

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A2	NM_000112.4	c.1474C>T	p.Arg492Trp	missense_variant	3/3	ENST00000286298.5
SLC26A2	XM_017009191.3	c.1474C>T	p.Arg492Trp	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A2	ENST00000286298.5	c.1474C>T	p.Arg492Trp	missense_variant	3/3	1	NM_000112.4	P1
SLC26A2	ENST00000503336.1	c.372+2716C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2405 AN: 152152 Hom.: 26 Cov.: 32

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.: 44 AF XY: 0.0168 AC XY: 2282 AN XY: 135796

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.: 34 AF XY: 0.0211 AC XY: 15365 AN XY: 727210

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.: 26 Cov.: 32 AF XY: 0.0152 AC XY: 1134 AN XY: 74458

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.: 67

Bravo AF: 0.0141

TwinsUK AF: 0.0251 AC: 93

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0217 AC: 187

ExAC AF: 0.0169 AC: 2052

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0241

EpiControl AF: 0.0216

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Eurofins Ntd Llc (ga)	Dec 16, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University 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. -

not provided Benign:3

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	Jan 01, 2024	SLC26A2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Diastrophic dysplasia Benign:2 Other: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. -
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. -

Multiple epiphyseal dysplasia type 4 Benign:2

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. -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Apr 10, 2014	- -

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

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

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	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.24
MPC		0.33
ClinPred		0.024	T
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

Other links and lift over

dbSNP: rs78676079; hg19: chr5-149360630; COSMIC: COSV53825620; COSMIC: COSV53825620;