rs56398830

chr13-103049340-G-Achr13-103049340-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS2

The NM_000452.3(SLC10A2):c.868C>T(p.Pro290Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,613,978 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P290L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0087 (10 hom., cov: 32)
  • Exomes 𝑓: 0.011 (120 hom.)
• Consequence: SLC10A2 NM_000452.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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 Benign. Variant got -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, BayesDel_noAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0128285885).
• BP6: Variant 13-103049340-G-A is Benign according to our data. Variant chr13-103049340-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 374538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 1330 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC10A2	NM_000452.3	c.868C>T	p.Pro290Ser	missense_variant	5/6	ENST00000245312.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC10A2	ENST00000245312.5	c.868C>T	p.Pro290Ser	missense_variant	5/6	1	NM_000452.3	P1

Frequencies

GnomAD3 genomes AF: 0.00874 AC: 1330 AN: 152164 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00998 AC: 2508 AN: 251256 Hom.: 25 AF XY: 0.0101 AC XY: 1367 AN XY: 135782

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0193

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.00716

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0106 AC: 15488 AN: 1461696 Hom.: 120 Cov.: 31 AF XY: 0.0105 AC XY: 7613 AN XY: 727162

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.0147

Gnomad4 ASJ exome AF: 0.0163

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00153

Gnomad4 FIN exome AF: 0.00629

Gnomad4 NFE exome AF: 0.0118

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.00873 AC: 1329 AN: 152282 Hom.: 10 Cov.: 32 AF XY: 0.00826 AC XY: 615 AN XY: 74456

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.0159

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00706

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.0119 Hom.: 15

Bravo AF: 0.00960

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0119 AC: 102

ExAC AF: 0.00955 AC: 1159

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0155

EpiControl AF: 0.0178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 22/2178=1% -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	SLC10A2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.011	D
Sift4G	Benign	0.069	T
Polyphen		0.99	D
Vest4		0.91
MVP		0.58
MPC		0.012
ClinPred		0.041	T
GERP RS		5.7
Varity_R		0.50
gMVP		0.91

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: rs56398830; hg19: chr13-103701690; COSMIC: COSV55357899;