rs59502379

Positions:

• chr12-21205999-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006446.5(SLCO1B1):​c.1463G>C​(p.Gly488Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00191 in 1,612,102 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (29 hom.)
• Consequence: SLCO1B1 NM_006446.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.91

Genes affected

SLCO1B1 (HGNC:10959): (solute carrier organic anion transporter family member 1B1) This gene encodes a liver-specific member of the organic anion transporter family. The encoded protein is a transmembrane receptor that mediates the sodium-independent uptake of numerous endogenous compounds including bilirubin, 17-beta-glucuronosyl estradiol and leukotriene C4. This protein is also involved in the removal of drug compounds such as statins, bromosulfophthalein and rifampin from the blood into the hepatocytes. Polymorphisms in the gene encoding this protein are associated with impaired transporter function. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016017199).
• BP6: Variant 12-21205999-G-C is Benign according to our data. Variant chr12-21205999-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 307954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21205999-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1541/151984) while in subpopulation AFR AF= 0.0353 (1464/41520). AF 95% confidence interval is 0.0338. There are 25 homozygotes in gnomad4. There are 715 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1541 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLCO1B1	NM_006446.5	c.1463G>C	p.Gly488Ala	missense_variant	11/15	ENST00000256958.3	NP_006437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLCO1B1	ENST00000256958.3	c.1463G>C	p.Gly488Ala	missense_variant	11/15	1	NM_006446.5	ENSP00000256958.2

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1536 AN: 151866 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00381

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00259 AC: 650 AN: 250838 Hom.: 10 AF XY: 0.00172 AC XY: 233 AN XY: 135556

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00106 AC: 1545 AN: 1460118 Hom.: 29 Cov.: 30 AF XY: 0.000863 AC XY: 627 AN XY: 726362

Gnomad4 AFR exome AF: 0.0394

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.0101 AC: 1541 AN: 151984 Hom.: 25 Cov.: 32 AF XY: 0.00963 AC XY: 715 AN XY: 74284

Gnomad4 AFR AF: 0.0353

Gnomad4 AMR AF: 0.00381

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00145 Hom.: 2

Bravo AF: 0.0114

ESP6500AA AF: 0.0352 AC: 155

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00320 AC: 388

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rotor syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MVP		0.39
MPC		0.069
ClinPred		0.10	T
GERP RS		4.1
Varity_R		0.94
gMVP		0.83

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: rs59502379; hg19: chr12-21358933;