rs71640248

Variant names:

• chr13-103049322-A-G
• rs71640248
• NM_000452.3:c.886T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000452.3(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 the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0051 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (30 hom.)
• Consequence: SLC10A2 NM_000452.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.24
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• bile acid malabsorption, primary, 1

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 782336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000452.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC10A2	NM_000452.3	MANE Select	c.886T>C	p.Phe296Leu	missense	Exon 5 of 6	NP_000443.2	Q12908

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC10A2	ENST00000245312.5	TSL:1 MANE Select	c.886T>C	p.Phe296Leu	missense	Exon 5 of 6	ENSP00000245312.3	Q12908

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

GnomAD2 exomes AF: 0.00464 AC: 1165 AN: 251152 AF XY: 0.00456

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 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

African (AFR) AF: 0.000687 AC: 23 AN: 33472

American (AMR) AF: 0.00331 AC: 148 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00850 AC: 222 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0104 AC: 556 AN: 53406

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00569 AC: 6331 AN: 1111858

Other (OTH) AF: 0.00412 AC: 249 AN: 60374

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

African (AFR) AF: 0.000914 AC: 38 AN: 41566

American (AMR) AF: 0.00307 AC: 47 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0126 AC: 134 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00746 AC: 507 AN: 68000

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00586 Hom.: 8

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.2
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
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

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