2-43877786-T-C

Variant names:

• chr2-43877786-T-C
• rs6544718
• NM_022437.3:c.1895T>C

Variant summary

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

The NM_022437.3(ABCG8):​c.1895T>C​(p.Val632Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.804 in 1,614,012 control chromosomes in the GnomAD database, including 524,666 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V632I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.85 (55907 hom., cov: 31)
  • Exomes 𝑓: 0.80 (468759 hom.)
• Consequence: ABCG8 NM_022437.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.176
• Publications: 74 publications found

Genes affected

ABCG8 (HGNC:13887): (ATP binding cassette subfamily G member 8) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the White subfamily. The protein encoded by this gene functions to exclude non-cholesterol sterol entry at the intestinal level, promote excretion of cholesterol and sterols into bile, and to facilitate transport of sterols back into the intestinal lumen. It is expressed in a tissue-specific manner in the liver, intestine, and gallbladder. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG5. Mutations in this gene may contribute to sterol accumulation and atherosclerosis, and have been observed in patients with sitosterolemia. [provided by RefSeq, Jul 2008]

ABCG8 Gene-Disease associations (from GenCC):

• sitosterolemia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
• sitosterolemia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=6.582935E-7).
• BP6: Variant 2-43877786-T-C is Benign according to our data. Variant chr2-43877786-T-C is described in ClinVar as Benign. ClinVar VariationId is 336092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022437.3. 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
	ABCG8	NM_022437.3	MANE Select	c.1895T>C	p.Val632Ala	missense	Exon 13 of 13	NP_071882.1
	ABCG8	NM_001357321.2		c.1892T>C	p.Val631Ala	missense	Exon 13 of 13	NP_001344250.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG8	ENST00000272286.4	TSL:1 MANE Select	c.1895T>C	p.Val632Ala	missense	Exon 13 of 13	ENSP00000272286.2

Frequencies

GnomAD3 genomes AF: 0.854 AC: 129817 AN: 152012 Hom.: 55852 Cov.: 31

Gnomad AFR AF: 0.960

Gnomad AMI AF: 0.850

Gnomad AMR AF: 0.841

Gnomad ASJ AF: 0.897

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.909

Gnomad FIN AF: 0.828

Gnomad MID AF: 0.895

Gnomad NFE AF: 0.779

Gnomad OTH AF: 0.872

GnomAD2 exomes AF: 0.842 AC: 211778 AN: 251446 AF XY: 0.842

Gnomad AFR exome AF: 0.963

Gnomad AMR exome AF: 0.846

Gnomad ASJ exome AF: 0.902

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.825

Gnomad NFE exome AF: 0.780

Gnomad OTH exome AF: 0.838

GnomAD4 exome AF: 0.798 AC: 1167146 AN: 1461882 Hom.: 468759 Cov.: 80 AF XY: 0.801 AC XY: 582385 AN XY: 727240

African (AFR) AF: 0.967 AC: 32386 AN: 33480

American (AMR) AF: 0.848 AC: 37924 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.893 AC: 23348 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39688 AN: 39700

South Asian (SAS) AF: 0.900 AC: 77606 AN: 86258

European-Finnish (FIN) AF: 0.824 AC: 44034 AN: 53418

Middle Eastern (MID) AF: 0.858 AC: 4950 AN: 5768

European-Non Finnish (NFE) AF: 0.771 AC: 857354 AN: 1112002

Other (OTH) AF: 0.825 AC: 49856 AN: 60396

GnomAD4 genome AF: 0.854 AC: 129930 AN: 152130 Hom.: 55907 Cov.: 31 AF XY: 0.857 AC XY: 63693 AN XY: 74360

African (AFR) AF: 0.960 AC: 39850 AN: 41500

American (AMR) AF: 0.841 AC: 12862 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.897 AC: 3116 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5169 AN: 5176

South Asian (SAS) AF: 0.908 AC: 4381 AN: 4824

European-Finnish (FIN) AF: 0.828 AC: 8754 AN: 10578

Middle Eastern (MID) AF: 0.880 AC: 257 AN: 292

European-Non Finnish (NFE) AF: 0.779 AC: 52921 AN: 67970

Other (OTH) AF: 0.874 AC: 1845 AN: 2112

Alfa AF: 0.808 Hom.: 153260

Bravo AF: 0.861

TwinsUK AF: 0.775 AC: 2873

ALSPAC AF: 0.771 AC: 2972

ESP6500AA AF: 0.947 AC: 4174

ESP6500EA AF: 0.781 AC: 6715

ExAC AF: 0.842 AC: 102224

Asia WGS AF: 0.958 AC: 3331 AN: 3478

EpiCase AF: 0.787

EpiControl AF: 0.786

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

May 14, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16980816, 11893785, 20581104)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sitosterolemia 1 Benign:2

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.

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Dec 03, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.0
DANN	Benign	0.58
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.060	T
MetaRNN	Benign	6.6e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
PhyloP100		0.18
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.021
Sift	Benign	0.89	T
Sift4G	Benign	0.84	T
Polyphen		0.0	B
Vest4		0.0090
MPC		0.016
ClinPred		0.00054	T
GERP RS		0.054
Varity_R		0.14
gMVP		0.25
Mutation Taster		=100/0	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: rs6544718; hg19: chr2-44104925; COSMIC: COSV107239268; COSMIC: COSV107239268;