rs61966074

Positions:

• chr13-103049298-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000452.3(SLC10A2):​c.910T>C​(p.Phe304Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,613,794 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (12 hom.)
• Consequence: SLC10A2 NM_000452.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.339

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075482726).
• BS2: High AC in GnomAd4 at 406 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC10A2	NM_000452.3	c.910T>C	p.Phe304Leu	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.910T>C	p.Phe304Leu	missense_variant	5/6	1	NM_000452.3	ENSP00000245312.3

Frequencies

GnomAD3 genomes AF: 0.00267 AC: 406 AN: 152184 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00239 AC: 600 AN: 251066 Hom.: 3 AF XY: 0.00229 AC XY: 310 AN XY: 135666

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00361

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00347

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00361 AC: 5277 AN: 1461492 Hom.: 12 Cov.: 31 AF XY: 0.00348 AC XY: 2530 AN XY: 727054

Gnomad4 AFR exome AF: 0.000867

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00120

Gnomad4 NFE exome AF: 0.00436

Gnomad4 OTH exome AF: 0.00273

GnomAD4 genome AF: 0.00267 AC: 406 AN: 152302 Hom.: 2 Cov.: 32 AF XY: 0.00205 AC XY: 153 AN XY: 74478

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00422

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00335 Hom.: 2

Bravo AF: 0.00280

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00251 AC: 305

EpiCase AF: 0.00420

EpiControl AF: 0.00302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -

Bile acid malabsorption, primary, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

SLC10A2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.0
DANN	Benign	0.74
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.040	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.019
Sift	Benign	0.36	T
Sift4G	Benign	0.99	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.38		Loss of sheet (P = 0.1907);
MVP		0.14
MPC		0.0047
ClinPred		0.0016	T
GERP RS		-0.079
Varity_R		0.033
gMVP		0.49

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: rs61966074; hg19: chr13-103701648;