12-21176804-A-G

Variant names:

• chr12-21176804-A-G
• rs2306283
• NM_006446.5:c.388A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006446.5(SLCO1B1):​c.388A>G​(p.Asn130Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 1,504,300 control chromosomes in the GnomAD database, including 143,945 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23489 hom., cov: 32)
  • Exomes 𝑓: 0.41 (120456 hom.)
• Consequence: SLCO1B1 NM_006446.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.275
• Publications: 543 publications found

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]

SLCO1B1 Gene-Disease associations (from GenCC):

• Rotor syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000257062 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6842818E-6).
• BP6: Variant 12-21176804-A-G is Benign according to our data. Variant chr12-21176804-A-G is described in ClinVar as Benign. ClinVar VariationId is 259983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006446.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1B1	NM_006446.5	MANE Select	c.388A>G	p.Asn130Asp	missense	Exon 5 of 15	NP_006437.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1B1	ENST00000256958.3	TSL:1 MANE Select	c.388A>G	p.Asn130Asp	missense	Exon 5 of 15	ENSP00000256958.2
	ENSG00000257062	ENST00000543498.5	TSL:4	n.*170A>G		non_coding_transcript_exon	Exon 6 of 6	ENSP00000454306.1
	ENSG00000257062	ENST00000543498.5	TSL:4	n.*170A>G		3_prime_UTR	Exon 6 of 6	ENSP00000454306.1

Frequencies

GnomAD3 genomes AF: 0.532 AC: 80757 AN: 151812 Hom.: 23449 Cov.: 32

Gnomad AFR AF: 0.768

Gnomad AMI AF: 0.683

Gnomad AMR AF: 0.469

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.512

GnomAD2 exomes AF: 0.474 AC: 118510 AN: 250172 AF XY: 0.466

Gnomad AFR exome AF: 0.776

Gnomad AMR exome AF: 0.433

Gnomad ASJ exome AF: 0.450

Gnomad EAS exome AF: 0.751

Gnomad FIN exome AF: 0.451

Gnomad NFE exome AF: 0.404

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.406 AC: 548628 AN: 1352370 Hom.: 120456 Cov.: 26 AF XY: 0.407 AC XY: 275414 AN XY: 676626

African (AFR) AF: 0.782 AC: 24668 AN: 31542

American (AMR) AF: 0.437 AC: 19332 AN: 44264

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 10935 AN: 24794

East Asian (EAS) AF: 0.702 AC: 27474 AN: 39110

South Asian (SAS) AF: 0.466 AC: 39522 AN: 84750

European-Finnish (FIN) AF: 0.442 AC: 22997 AN: 51984

Middle Eastern (MID) AF: 0.460 AC: 2517 AN: 5474

European-Non Finnish (NFE) AF: 0.371 AC: 376088 AN: 1014004

Other (OTH) AF: 0.445 AC: 25095 AN: 56448

GnomAD4 genome AF: 0.532 AC: 80854 AN: 151930 Hom.: 23489 Cov.: 32 AF XY: 0.535 AC XY: 39743 AN XY: 74250

African (AFR) AF: 0.768 AC: 31860 AN: 41484

American (AMR) AF: 0.470 AC: 7163 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1590 AN: 3464

East Asian (EAS) AF: 0.746 AC: 3852 AN: 5166

South Asian (SAS) AF: 0.516 AC: 2489 AN: 4824

European-Finnish (FIN) AF: 0.455 AC: 4810 AN: 10568

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.401 AC: 27245 AN: 67868

Other (OTH) AF: 0.514 AC: 1083 AN: 2108

Alfa AF: 0.451 Hom.: 55976

Bravo AF: 0.544

TwinsUK AF: 0.403 AC: 1495

ALSPAC AF: 0.397 AC: 1530

ESP6500AA AF: 0.765 AC: 3365

ESP6500EA AF: 0.404 AC: 3460

ExAC AF: 0.479 AC: 58132

Asia WGS AF: 0.656 AC: 2283 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rotor syndrome Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:3

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Gilbert syndrome Benign:1

May 01, 2019

Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing You An Hospital, Capital Medical University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: case-control

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.63
DANN	Benign	0.46
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.067	T
MetaRNN	Benign	0.0000017	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.60	N
PhyloP100		-0.28
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.023
Sift	Benign	0.45	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.010
ClinPred		0.0043	T
GERP RS		-2.6
Varity_R		0.051
gMVP		0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs2306283; hg19: chr12-21329738; COSMIC: COSV57012766;