NM_006446.5:c.521T>C

Variant names:

• chr12-21178615-T-C
• rs4149056
• NM_006446.5:c.521T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006446.5(SLCO1B1):​c.521T>C​(p.Val174Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,604,544 control chromosomes in the GnomAD database, including 17,896 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1424 hom., cov: 33)
  • Exomes 𝑓: 0.14 (16472 hom.)
• Consequence: SLCO1B1 NM_006446.5 missense
• Clinical Significance: drug response reviewed by expert panel P:1 B:8 O:16
• Conservation: PhyloP100: 7.58
• Publications: 1219 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025148094).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.156 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.521T>C	p.Val174Ala	missense	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.521T>C	p.Val174Ala	missense	Exon 6 of 15	ENSP00000256958.2
	SLCO1B1	ENST00000870182.1		c.521T>C	p.Val174Ala	missense	Exon 7 of 16	ENSP00000540241.1
	SLCO1B1	ENST00000870184.1		c.521T>C	p.Val174Ala	missense	Exon 7 of 16	ENSP00000540243.1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18322 AN: 152086 Hom.: 1425 Cov.: 33

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.0489

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.137

GnomAD2 exomes AF: 0.133 AC: 33347 AN: 250964 AF XY: 0.130

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.126

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.145 AC: 209991 AN: 1452340 Hom.: 16472 Cov.: 29 AF XY: 0.142 AC XY: 103001 AN XY: 723244

African (AFR) AF: 0.0305 AC: 1016 AN: 33352

American (AMR) AF: 0.120 AC: 5383 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4805 AN: 26044

East Asian (EAS) AF: 0.139 AC: 5482 AN: 39570

South Asian (SAS) AF: 0.0470 AC: 4047 AN: 86102

European-Finnish (FIN) AF: 0.207 AC: 11034 AN: 53400

Middle Eastern (MID) AF: 0.205 AC: 1175 AN: 5730

European-Non Finnish (NFE) AF: 0.152 AC: 168145 AN: 1103384

Other (OTH) AF: 0.148 AC: 8904 AN: 60062

GnomAD4 genome AF: 0.120 AC: 18320 AN: 152204 Hom.: 1424 Cov.: 33 AF XY: 0.124 AC XY: 9200 AN XY: 74404

African (AFR) AF: 0.0316 AC: 1315 AN: 41572

American (AMR) AF: 0.130 AC: 1992 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 615 AN: 3472

East Asian (EAS) AF: 0.127 AC: 660 AN: 5180

South Asian (SAS) AF: 0.0487 AC: 235 AN: 4824

European-Finnish (FIN) AF: 0.218 AC: 2302 AN: 10568

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10792 AN: 67982

Other (OTH) AF: 0.135 AC: 285 AN: 2114

Alfa AF: 0.141 Hom.: 5531

Bravo AF: 0.111

TwinsUK AF: 0.156 AC: 580

ALSPAC AF: 0.144 AC: 554

ESP6500AA AF: 0.0361 AC: 159

ESP6500EA AF: 0.155 AC: 1336

ExAC AF: 0.129 AC: 15704

Asia WGS AF: 0.0920 AC: 318 AN: 3476

EpiCase AF: 0.160

EpiControl AF: 0.154

ClinVar

ClinVar submissions as Germline

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	Rotor syndrome (3)
1	-	-	Gilbert syndrome (1)
-	-	1	not provided (2)
-	-	1	SLCO1B1-related disorder (1)
-	-	-	atorvastatin response - Metabolism/PK (1)
-	-	-	atorvastatin response - Toxicity (1)
-	-	-	fluvastatin response - Metabolism/PK (1)
-	-	-	fluvastatin response - Toxicity (1)
-	-	-	hmg coa reductase inhibitors response - Toxicity (1)
-	-	-	lovastatin acid response - Metabolism/PK (1)
-	-	-	lovastatin response - Metabolism/PK (1)
-	-	-	lovastatin response - Toxicity (1)
-	-	-	pitavastatin response - Metabolism/PK (1)
-	-	-	pravastatin response - Toxicity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.24
MPC		0.066
ClinPred		0.064	T
GERP RS		3.6
Varity_R		0.86
gMVP		0.60
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4149056; hg19: chr12-21331549; COSMIC: COSV57010105; COSMIC: COSV57010105;