rs71640248

Positions:

• chr13-103049322-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000245312.5(SLC10A2):​c.886T>C​(p.Phe296Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00515 in 1,613,940 control chromosomes in the GnomAD database, including 35 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 ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0051 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (30 hom.)
• Consequence: SLC10A2 ENST00000245312.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.24

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016042888).
• BP6: Variant 13-103049322-A-G is Benign according to our data. Variant chr13-103049322-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 782336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-103049322-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 782 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC10A2	NM_000452.3	c.886T>C	p.Phe296Leu	missense_variant	5/6	ENST00000245312.5	NP_000443.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC10A2	ENST00000245312.5	c.886T>C	p.Phe296Leu	missense_variant	5/6	1	NM_000452.3	ENSP00000245312	P1

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 782 AN: 152154 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00746

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00464 AC: 1165 AN: 251152 Hom.: 4 AF XY: 0.00456 AC XY: 619 AN XY: 135728

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00755

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.00605

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00515 AC: 7534 AN: 1461668 Hom.: 30 Cov.: 31 AF XY: 0.00509 AC XY: 3700 AN XY: 727144

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00331

Gnomad4 ASJ exome AF: 0.00850

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0104

Gnomad4 NFE exome AF: 0.00569

Gnomad4 OTH exome AF: 0.00412

GnomAD4 genome AF: 0.00514 AC: 782 AN: 152272 Hom.: 5 Cov.: 32 AF XY: 0.00518 AC XY: 386 AN XY: 74462

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.00746

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00701 Hom.: 5

Bravo AF: 0.00393

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.00429 AC: 521

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00687

EpiControl AF: 0.00528

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	SLC10A2: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.87	P
Vest4		0.92
MutPred		0.61		Loss of catalytic residue at F296 (P = 0.3161);
MVP		0.59
MPC		0.0052
ClinPred		0.048	T
GERP RS		5.7
Varity_R		0.58
gMVP		0.74

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: rs71640248; hg19: chr13-103701672; COSMIC: COSV55361440;