chr2-43872255-C-A

Position:

• chr2-43872255-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022437.3(ABCG8):​c.1160C>A​(p.Pro387Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P387L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCG8 NM_022437.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.89

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0576649).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCG8	NM_022437.3	c.1160C>A	p.Pro387Gln	missense_variant	8/13	ENST00000272286.4	NP_071882.1
ABCG8	NM_001357321.2	c.1157C>A	p.Pro386Gln	missense_variant	8/13		NP_001344250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCG8	ENST00000272286.4	c.1160C>A	p.Pro387Gln	missense_variant	8/13	1	NM_022437.3	ENSP00000272286	P1
ABCG8	ENST00000644611.1	c.1172C>A	p.Pro391Gln	missense_variant	8/9			ENSP00000495423

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.0050
DANN	Benign	0.45
DEOGEN2	Benign	0.24	.;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.31	T;.;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.058	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	-0.60	.;N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.34	.;.;N
REVEL	Benign	0.13
Sift	Benign	0.61	.;.;T
Sift4G	Benign	0.62	.;.;T
Polyphen		0.0060	.;B;B
Vest4		0.10
MutPred		0.29		.;Loss of glycosylation at T390 (P = 0.0775);Loss of glycosylation at T390 (P = 0.0775);
MVP		0.43
MPC		0.015
ClinPred		0.062	T
GERP RS		-9.6
Varity_R		0.023
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150654176; hg19: chr2-44099394; COSMIC: COSV55397971;