12-21178691-C-T

Variant names:

• chr12-21178691-C-T
• rs2291075
• NM_006446.5:c.597C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006446.5(SLCO1B1):​c.597C>T​(p.Phe199Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,596,296 control chromosomes in the GnomAD database, including 124,806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15295 hom., cov: 32)
  • Exomes 𝑓: 0.38 (109511 hom.)
• Consequence: SLCO1B1 NM_006446.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.437
• Publications: 83 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 12-21178691-C-T is Benign according to our data. Variant chr12-21178691-C-T is described in ClinVar as Benign. ClinVar VariationId is 259985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.437 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.546 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1B1	NM_006446.5	MANE Select	c.597C>T	p.Phe199Phe	synonymous	Exon 6 of 15	NP_006437.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1B1	ENST00000256958.3	TSL:1 MANE Select	c.597C>T	p.Phe199Phe	synonymous	Exon 6 of 15	ENSP00000256958.2	Q9Y6L6
	SLCO1B1	ENST00000870182.1		c.597C>T	p.Phe199Phe	synonymous	Exon 7 of 16	ENSP00000540241.1
	SLCO1B1	ENST00000870184.1		c.597C>T	p.Phe199Phe	synonymous	Exon 7 of 16	ENSP00000540243.1

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66785 AN: 151814 Hom.: 15285 Cov.: 32

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.663

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.498

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.429

GnomAD2 exomes AF: 0.382 AC: 95936 AN: 251052 AF XY: 0.373

Gnomad AFR exome AF: 0.552

Gnomad AMR exome AF: 0.265

Gnomad ASJ exome AF: 0.458

Gnomad EAS exome AF: 0.519

Gnomad FIN exome AF: 0.460

Gnomad NFE exome AF: 0.398

Gnomad OTH exome AF: 0.409

GnomAD4 exome AF: 0.382 AC: 551781 AN: 1444364 Hom.: 109511 Cov.: 33 AF XY: 0.377 AC XY: 271186 AN XY: 719642

African (AFR) AF: 0.560 AC: 18556 AN: 33134

American (AMR) AF: 0.278 AC: 12426 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 11972 AN: 25990

East Asian (EAS) AF: 0.440 AC: 17399 AN: 39564

South Asian (SAS) AF: 0.191 AC: 16396 AN: 86054

European-Finnish (FIN) AF: 0.457 AC: 24403 AN: 53400

Middle Eastern (MID) AF: 0.436 AC: 2488 AN: 5712

European-Non Finnish (NFE) AF: 0.387 AC: 423868 AN: 1096012

Other (OTH) AF: 0.406 AC: 24273 AN: 59824

GnomAD4 genome AF: 0.440 AC: 66837 AN: 151932 Hom.: 15295 Cov.: 32 AF XY: 0.439 AC XY: 32601 AN XY: 74238

African (AFR) AF: 0.552 AC: 22884 AN: 41452

American (AMR) AF: 0.352 AC: 5371 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1577 AN: 3466

East Asian (EAS) AF: 0.498 AC: 2566 AN: 5154

South Asian (SAS) AF: 0.211 AC: 1018 AN: 4820

European-Finnish (FIN) AF: 0.462 AC: 4863 AN: 10534

Middle Eastern (MID) AF: 0.473 AC: 138 AN: 292

European-Non Finnish (NFE) AF: 0.396 AC: 26910 AN: 67934

Other (OTH) AF: 0.429 AC: 905 AN: 2108

Alfa AF: 0.412 Hom.: 29588

Bravo AF: 0.441

Asia WGS AF: 0.355 AC: 1233 AN: 3476

EpiCase AF: 0.401

EpiControl AF: 0.406

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Rotor syndrome (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	SLCO1B1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	10
DANN	Benign	0.67
PhyloP100		0.44
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: rs2291075; hg19: chr12-21331625; COSMIC: COSV57010363; COSMIC: COSV57010363;