2-43877786-T-C

Position:

• chr2-43877786-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:11
• Conservation: PhyloP100: 0.176

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 336092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-43877786-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCG8	NM_022437.3	c.1895T>C	p.Val632Ala	missense_variant	13/13	ENST00000272286.4	NP_071882.1
ABCG8	NM_001357321.2	c.1892T>C	p.Val631Ala	missense_variant	13/13		NP_001344250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCG8	ENST00000272286.4	c.1895T>C	p.Val632Ala	missense_variant	13/13	1	NM_022437.3	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

GnomAD3 exomes AF: 0.842 AC: 211778 AN: 251446 Hom.: 89999 AF XY: 0.842 AC XY: 114416 AN XY: 135892

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 SAS exome AF: 0.903

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

Gnomad4 AFR exome AF: 0.967

Gnomad4 AMR exome AF: 0.848

Gnomad4 ASJ exome AF: 0.893

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.900

Gnomad4 FIN exome AF: 0.824

Gnomad4 NFE exome AF: 0.771

Gnomad4 OTH exome AF: 0.825

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

Gnomad4 AFR AF: 0.960

Gnomad4 AMR AF: 0.841

Gnomad4 ASJ AF: 0.897

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.908

Gnomad4 FIN AF: 0.828

Gnomad4 NFE AF: 0.779

Gnomad4 OTH AF: 0.874

Alfa AF: 0.802 Hom.: 110465

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	This variant is associated with the following publications: (PMID: 16980816, 11893785, 20581104) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Sitosterolemia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2018

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 v4.3

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;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;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N;N
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;B
Vest4		0.0090
MPC		0.016
ClinPred		0.00054	T
GERP RS		0.054
Varity_R		0.14
gMVP		0.25

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: rs6544718; hg19: chr2-44104925;