rs72547505

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000452.3(SLC10A2):c.785C>T(p.Thr262Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,613,904 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00051 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 0 hom. )

Consequence

SLC10A2
NM_000452.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 9.91

Variant links:

Genes affected

SLC10A2 (HGNC:10906): (solute carrier family 10 member 2) This gene encodes a sodium/bile acid cotransporter. This transporter is the primary mechanism for uptake of intestinal bile acids by apical cells in the distal ileum. Bile acids are the catabolic product of cholesterol metabolism, so this protein is also critical for cholesterol homeostasis. Mutations in this gene cause primary bile acid malabsorption (PBAM); muatations in this gene may also be associated with other diseases of the liver and intestines, such as familial hypertriglyceridemia (FHTG). [provided by RefSeq, Mar 2010]

SLC10A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 78 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC10A2	NM_000452.3 linkuse as main transcript	c.785C>T	p.Thr262Met	missense_variant	5/6	ENST00000245312.5	NP_000443.2	Q12908

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC10A2	ENST00000245312.5 linkuse as main transcript	c.785C>T	p.Thr262Met	missense_variant	5/6	1	NM_000452.3	ENSP00000245312.3		Q12908

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000529

AC:

133

AN:

251356

Hom.:

AF XY:

0.000567

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.000327

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.000712

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000494

AC:

722

AN:

1461704

Hom.:

Cov.:

AF XY:

0.000503

AC XY:

366

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00256

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.000356

Gnomad4 NFE exome

AF:

0.000500

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.000512

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000676

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000726

Hom.:

Bravo

AF:

0.000574

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000511

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 09, 2023	PP3, PS3 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 07, 2023	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2018	- -

Bile acid malabsorption, primary, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 14, 2024

- -

SLC10A2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2024

The SLC10A2 c.785C>T variant is predicted to result in the amino acid substitution p.Thr262Met. This variant was reported in a single individual with autosomal recessive primary bile acid malabsorption, but it was detected in cis (on the same chromosome) with a more rare variant (Oelkers et al. 1997. PubMed ID: 9109432). Functional studies have supported the pathogenicity of both changes alone, and as a complex allele, thus not allowing definitive conclusions about which may be causative (Ho et al. 2011. PubMed ID: 21649730). In ClinVar, this variant is interpreted by the majority of submitting laboratories as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/242727/evidence/). This variant is reported in 0.26% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.57

MetaSVM

Uncertain

0.35

MutationAssessor

Pathogenic

3.3

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.6

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.93

MPC

0.022

ClinPred

0.27

GERP RS

5.7

Varity_R

0.74

gMVP

0.97

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