rs35518570

Positions:

• chr2-43852680-C-A
• chr2-43852680-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022437.3(ABCG8):​c.776C>A​(p.Ala259Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. A259V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCG8 NM_022437.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCG8	NM_022437.3	c.776C>A	p.Ala259Asp	missense_variant	6/13	ENST00000272286.4	NP_071882.1
ABCG8	NM_001357321.2	c.776C>A	p.Ala259Asp	missense_variant	6/13		NP_001344250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCG8	ENST00000272286.4	c.776C>A	p.Ala259Asp	missense_variant	6/13	1	NM_022437.3	ENSP00000272286.2
ABCG8	ENST00000644611.1	c.788C>A	p.Ala263Asp	missense_variant	6/9			ENSP00000495423.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.4	.;M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.3	.;.;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0020	.;.;D
Sift4G	Uncertain	0.0070	.;.;D
Polyphen		1.0	.;D;D
Vest4		0.97
MutPred		0.61		.;Loss of MoRF binding (P = 0.0623);Loss of MoRF binding (P = 0.0623);
MVP		0.46
MPC		0.13
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.94
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35518570; hg19: chr2-44079819;