12-21295769-A-C

Position:

• chr12-21295769-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001386879.1(SLCO1A2):​c.1099T>G​(p.Cys367Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,206 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SLCO1A2 NM_001386879.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37

Genes affected

SLCO1A2 (HGNC:10956): (solute carrier organic anion transporter family member 1A2) This gene encodes a sodium-independent transporter which mediates cellular uptake of organic ions in the liver. Its substrates include bile acids, bromosulphophthalein, and some steroidal compounds. The protein is a member of the SLC21A family of solute carriers. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLCO1A2	NM_001386879.1	c.1099T>G	p.Cys367Gly	missense_variant	10/15	ENST00000683939.1	NP_001373808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLCO1A2	ENST00000683939.1	c.1099T>G	p.Cys367Gly	missense_variant	10/15		NM_001386879.1	ENSP00000508235.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398206 Hom.: 0 Cov.: 25 AF XY: 0.00000143 AC XY: 1 AN XY: 698242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.44e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2024

The c.1099T>G (p.C367G) alteration is located in exon 9 (coding exon 9) of the SLCO1A2 gene. This alteration results from a T to G substitution at nucleotide position 1099, causing the cysteine (C) at amino acid position 367 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.35
Sift	Benign	0.15	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.012	B;.
Vest4		0.75
MutPred		0.58		Gain of catalytic residue at P365 (P = 0);.;
MVP		0.56
MPC		0.22
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.44
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs772700890; hg19: chr12-21448703;