rs35518570

Variant names:

• chr2-43852680-C-A
• rs35518570
• NM_022437.3:c.776C>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCG8 NM_022437.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50
• Publications: 5 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: Illumina, ClinGen, Orphanet
• sitosterolemia 1

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG8	NM_022437.3	MANE Select	c.776C>A	p.Ala259Asp	missense	Exon 6 of 13	NP_071882.1	Q9H221-1
	ABCG8	NM_001357321.2		c.776C>A	p.Ala259Asp	missense	Exon 6 of 13	NP_001344250.1	Q9H221-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG8	ENST00000272286.4	TSL:1 MANE Select	c.776C>A	p.Ala259Asp	missense	Exon 6 of 13	ENSP00000272286.2	Q9H221-1
	ABCG8	ENST00000881895.1		c.776C>A	p.Ala259Asp	missense	Exon 6 of 13	ENSP00000551954.1
	ABCG8	ENST00000881900.1		c.776C>A	p.Ala259Asp	missense	Exon 6 of 13	ENSP00000551959.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
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
Vest4		0.97
MutPred		0.61		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
Mutation Taster		=13/87	disease causing

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

Other links and lift over

dbSNP: rs35518570; hg19: chr2-44079819;