chr5-149981314-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_000112.4(SLC26A2):c.1721T>C(p.Ile574Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,614,158 control chromosomes in the GnomAD database, including 791,001 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.99 ( 75125 hom., cov: 32)

Exomes 𝑓: 0.99 ( 715876 hom. )

Consequence

SLC26A2
NM_000112.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 1.69

Publications

38 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: Benign. The variant received -17 ACMG points.

PM1

In a domain STAS (size 151) in uniprot entity S26A2_HUMAN there are 11 pathogenic changes around while only 3 benign (79%) in NM_000112.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 0.031413 (below the threshold of 3.09). Trascript score misZ: 1.4892 (below the threshold of 3.09). GenCC associations: The gene is linked to multiple epiphyseal dysplasia type 4, atelosteogenesis type II, achondrogenesis type IB, diastrophic dysplasia, multiple epiphyseal dysplasia.

BP4

Computational evidence support a benign effect (MetaRNN=2.4856772E-6).

BP6

Variant 5-149981314-T-C is Benign according to our data. Variant chr5-149981314-T-C is described in ClinVar as Benign. ClinVar VariationId is 196209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A2	NM_000112.4 link	c.1721T>C	p.Ile574Thr	missense_variant	Exon 3 of 3	ENST00000286298.5	NP_000103.2	P50443
SLC26A2	XM_017009191.3 link	c.1721T>C	p.Ile574Thr	missense_variant	Exon 3 of 4		XP_016864680.1	P50443

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A2	ENST00000286298.5 link	c.1721T>C	p.Ile574Thr	missense_variant	Exon 3 of 3	1	NM_000112.4	ENSP00000286298.4		P50443
SLC26A2	ENST00000503336.1 link	c.372+2963T>C		intron_variant	Intron 1 of 1	3		ENSP00000426053.1		H0YA38

Frequencies

GnomAD3 genomes

AF:

0.993

AC:

151159

AN:

152200

Hom.:

75063

Cov.:

show subpopulations

Gnomad AFR

AF:

0.998

Gnomad AMI

AF:

0.993

Gnomad AMR

AF:

0.995

Gnomad ASJ

AF:

0.993

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.993

Gnomad FIN

AF:

0.998

Gnomad MID

AF:

0.984

Gnomad NFE

AF:

0.988

Gnomad OTH

AF:

0.994

GnomAD2 exomes

AF:

0.993

AC:

249577

AN:

251316

AF XY:

0.993

show subpopulations

Gnomad AFR exome

AF:

0.998

Gnomad AMR exome

AF:

0.997

Gnomad ASJ exome

AF:

0.993

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.998

Gnomad NFE exome

AF:

0.989

Gnomad OTH exome

AF:

0.993

GnomAD4 exome

AF:

0.990

AC:

1446695

AN:

1461840

Hom.:

715876

Cov.:

AF XY:

0.990

AC XY:

719789

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.998

AC:

33422

AN:

33480

American (AMR)

AF:

0.997

AC:

44607

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.993

AC:

25941

AN:

26134

East Asian (EAS)

AF:

1.00

AC:

39696

AN:

39698

South Asian (SAS)

AF:

0.995

AC:

85789

AN:

86256

European-Finnish (FIN)

AF:

0.997

AC:

53256

AN:

53410

Middle Eastern (MID)

AF:

0.997

AC:

5751

AN:

5768

European-Non Finnish (NFE)

AF:

0.988

AC:

1098362

AN:

1111976

Other (OTH)

AF:

0.991

AC:

59871

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

925

1851

2776

3702

4627

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21668

43336

65004

86672

108340

<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:

0.993

AC:

151280

AN:

152318

Hom.:

75125

Cov.:

AF XY:

0.993

AC XY:

74005

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.998

AC:

41477

AN:

41556

American (AMR)

AF:

0.995

AC:

15216

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.993

AC:

3447

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5190

AN:

5190

South Asian (SAS)

AF:

0.993

AC:

4797

AN:

4830

European-Finnish (FIN)

AF:

0.998

AC:

10600

AN:

10618

Middle Eastern (MID)

AF:

0.990

AC:

291

AN:

294

European-Non Finnish (NFE)

AF:

0.988

AC:

67253

AN:

68038

Other (OTH)

AF:

0.995

AC:

2103

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

106

160

213

266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

916

1832

2748

3664

4580

<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:

0.991

Hom.:

213554

Bravo

AF:

0.993

TwinsUK

AF:

0.987

AC:

3660

ALSPAC

AF:

0.987

AC:

3804

ESP6500AA

AF:

0.998

AC:

4397

ESP6500EA

AF:

0.991

AC:

8519

ExAC

AF:

0.993

AC:

120534

Asia WGS

AF:

0.997

AC:

3469

AN:

3478

EpiCase

AF:

0.990

EpiControl

AF:

0.990

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 18, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Achondrogenesis, type IB

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:2

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 29, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Atelosteogenesis type II

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Multiple epiphyseal dysplasia type 4

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sulfate transporter-related osteochondrodysplasia

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diastrophic dysplasia

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Connective tissue disorder

Benign:1

Jul 18, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.14

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.0099

MetaRNN

Benign

0.0000025

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.6

PhyloP100

1.7

PrimateAI

Benign

0.36

PROVEAN

Benign

2.9

REVEL

Benign

0.15

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.026

MPC

0.055

ClinPred

0.00055

GERP RS

4.4

Varity_R

0.034

gMVP

0.20

Mutation Taster

=100/0

polymorphism (auto)

(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