rs72547505

Positions:

• chr13-103049423-G-A
• chr13-103049423-G-T

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T262K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: SLC10A2 NM_000452.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 9.91

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]

ACMG classification

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	UniProt
SLC10A2	NM_000452.3	c.785C>T	p.Thr262Met	missense_variant	5/6	ENST00000245312.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC10A2	ENST00000245312.5	c.785C>T	p.Thr262Met	missense_variant	5/6	1	NM_000452.3	P1

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152082 Hom.: 1 Cov.: 32

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.: 0 AF XY: 0.000567 AC XY: 77 AN XY: 135842

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.: 0 Cov.: 31 AF XY: 0.000503 AC XY: 366 AN XY: 727154

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: 78 AN: 152200 Hom.: 1 Cov.: 32 AF XY: 0.000605 AC XY: 45 AN XY: 74420

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.: 0

Bravo AF: 0.000574

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000511 AC: 62

EpiCase AF: 0.00104

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 09, 2023	PP3, PS3 -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 07, 2023	- -
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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 14, 2023

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 alteration is interpreted as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/242727/evidence/). Although it's possible that this variant could be pathogenic, its clinical significance remains uncertain at this time due to insufficient functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.93
MPC		0.022
ClinPred		0.27	T
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

Other links and lift over

dbSNP: rs72547505; hg19: chr13-103701773;