NM_022437.3:c.1895T>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: Illumina, ClinGen, Orphanet
• 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

Sel.	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	Q9H221-1
	ABCG8	NM_001357321.2		c.1892T>C	p.Val631Ala	missense	Exon 13 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.1895T>C	p.Val632Ala	missense	Exon 13 of 13	ENSP00000272286.2	Q9H221-1
	ABCG8	ENST00000881895.1		c.1910T>C	p.Val637Ala	missense	Exon 13 of 13	ENSP00000551954.1
	ABCG8	ENST00000881900.1		c.1907T>C	p.Val636Ala	missense	Exon 13 of 13	ENSP00000551959.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Sitosterolemia 1 (2)
-	-	1	Cardiovascular phenotype (1)

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;