rs4148217

Variant names:

• chr2-43872294-C-A
• rs4148217
• NM_022437.3:c.1199C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-43872294-C-A
• chr2-43872294-C-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_022437.3(ABCG8):​c.1199C>A​(p.Thr400Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,613,206 control chromosomes in the GnomAD database, including 31,756 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T400M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.22 (3926 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27830 hom.)
• Consequence: ABCG8 NM_022437.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.85
• Publications: 107 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_022437.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.005831182).
• BP6: Variant 2-43872294-C-A is Benign according to our data. Variant chr2-43872294-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.275 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.1199C>A	p.Thr400Lys	missense	Exon 8 of 13	NP_071882.1	Q9H221-1
	ABCG8	NM_001357321.2		c.1196C>A	p.Thr399Lys	missense	Exon 8 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.1199C>A	p.Thr400Lys	missense	Exon 8 of 13	ENSP00000272286.2	Q9H221-1
	ABCG8	ENST00000881895.1		c.1199C>A	p.Thr400Lys	missense	Exon 8 of 13	ENSP00000551954.1
	ABCG8	ENST00000881900.1		c.1196C>A	p.Thr399Lys	missense	Exon 8 of 13	ENSP00000551959.1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33571 AN: 151940 Hom.: 3916 Cov.: 32

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.229

GnomAD2 exomes AF: 0.212 AC: 52929 AN: 250160 AF XY: 0.202

Gnomad AFR exome AF: 0.284

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.107

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.190

Gnomad OTH exome AF: 0.213

GnomAD4 exome AF: 0.190 AC: 278140 AN: 1461148 Hom.: 27830 Cov.: 36 AF XY: 0.188 AC XY: 136853 AN XY: 726846

African (AFR) AF: 0.288 AC: 9636 AN: 33454

American (AMR) AF: 0.342 AC: 15256 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 5963 AN: 26132

East Asian (EAS) AF: 0.118 AC: 4682 AN: 39680

South Asian (SAS) AF: 0.147 AC: 12657 AN: 86240

European-Finnish (FIN) AF: 0.217 AC: 11540 AN: 53178

Middle Eastern (MID) AF: 0.182 AC: 1049 AN: 5768

European-Non Finnish (NFE) AF: 0.184 AC: 205049 AN: 1111698

Other (OTH) AF: 0.204 AC: 12308 AN: 60366

GnomAD4 genome AF: 0.221 AC: 33612 AN: 152058 Hom.: 3926 Cov.: 32 AF XY: 0.223 AC XY: 16558 AN XY: 74310

African (AFR) AF: 0.280 AC: 11589 AN: 41448

American (AMR) AF: 0.276 AC: 4214 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 779 AN: 3468

East Asian (EAS) AF: 0.112 AC: 580 AN: 5170

South Asian (SAS) AF: 0.150 AC: 724 AN: 4822

European-Finnish (FIN) AF: 0.219 AC: 2310 AN: 10562

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.187 AC: 12723 AN: 68000

Other (OTH) AF: 0.229 AC: 483 AN: 2110

Alfa AF: 0.192 Hom.: 5968

Bravo AF: 0.232

TwinsUK AF: 0.182 AC: 675

ALSPAC AF: 0.173 AC: 666

ESP6500AA AF: 0.273 AC: 1202

ESP6500EA AF: 0.192 AC: 1647

ExAC AF: 0.207 AC: 25115

Asia WGS AF: 0.189 AC: 658 AN: 3478

EpiCase AF: 0.190

EpiControl AF: 0.187

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	0.13
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.99	L
PhyloP100		1.8
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.053
Sift	Benign	0.27	T
Sift4G	Benign	0.34	T
Polyphen		0.059	B
Vest4		0.20
MPC		0.017
ClinPred		0.0071	T
GERP RS		3.9
Varity_R		0.18
gMVP		0.58
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4148217; hg19: chr2-44099433; COSMIC: COSV55393511;