rs4148211

Variant names:

• chr2-43844604-A-G
• rs4148211
• NM_022437.3:c.161A>G

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.161A>G​(p.Tyr54Cys) variant causes a missense change. The variant allele was found at a frequency of 0.402 in 1,609,778 control chromosomes in the GnomAD database, including 138,441 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11209 hom., cov: 32)
  • Exomes 𝑓: 0.41 (127232 hom.)
• Consequence: ABCG8 NM_022437.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.21
• Publications: 92 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

ENSG00000305165 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0526757E-6).
• BP6: Variant 2-43844604-A-G is Benign according to our data. Variant chr2-43844604-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 288558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.837 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.161A>G	p.Tyr54Cys	missense	Exon 2 of 13	NP_071882.1	Q9H221-1
	ABCG8	NM_001357321.2		c.161A>G	p.Tyr54Cys	missense	Exon 2 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.161A>G	p.Tyr54Cys	missense	Exon 2 of 13	ENSP00000272286.2	Q9H221-1
	ABCG8	ENST00000881895.1		c.161A>G	p.Tyr54Cys	missense	Exon 2 of 13	ENSP00000551954.1
	ABCG8	ENST00000881900.1		c.161A>G	p.Tyr54Cys	missense	Exon 2 of 13	ENSP00000551959.1

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54458 AN: 151858 Hom.: 11196 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.858

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.348

GnomAD2 exomes AF: 0.429 AC: 107424 AN: 250470 AF XY: 0.434

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.391

Gnomad ASJ exome AF: 0.368

Gnomad EAS exome AF: 0.871

Gnomad FIN exome AF: 0.449

Gnomad NFE exome AF: 0.384

Gnomad OTH exome AF: 0.401

GnomAD4 exome AF: 0.407 AC: 593182 AN: 1457802 Hom.: 127232 Cov.: 32 AF XY: 0.410 AC XY: 297397 AN XY: 725404

African (AFR) AF: 0.182 AC: 6085 AN: 33412

American (AMR) AF: 0.389 AC: 17363 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 9751 AN: 26114

East Asian (EAS) AF: 0.850 AC: 33722 AN: 39650

South Asian (SAS) AF: 0.508 AC: 43723 AN: 86132

European-Finnish (FIN) AF: 0.446 AC: 23784 AN: 53354

Middle Eastern (MID) AF: 0.305 AC: 1757 AN: 5764

European-Non Finnish (NFE) AF: 0.391 AC: 433035 AN: 1108488

Other (OTH) AF: 0.398 AC: 23962 AN: 60262

GnomAD4 genome AF: 0.358 AC: 54472 AN: 151976 Hom.: 11209 Cov.: 32 AF XY: 0.368 AC XY: 27316 AN XY: 74276

African (AFR) AF: 0.196 AC: 8127 AN: 41452

American (AMR) AF: 0.370 AC: 5648 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1293 AN: 3468

East Asian (EAS) AF: 0.858 AC: 4425 AN: 5156

South Asian (SAS) AF: 0.532 AC: 2557 AN: 4806

European-Finnish (FIN) AF: 0.454 AC: 4793 AN: 10552

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.390 AC: 26478 AN: 67944

Other (OTH) AF: 0.354 AC: 747 AN: 2112

Alfa AF: 0.386 Hom.: 54167

Bravo AF: 0.343

TwinsUK AF: 0.376 AC: 1394

ALSPAC AF: 0.396 AC: 1527

ESP6500AA AF: 0.195 AC: 860

ESP6500EA AF: 0.385 AC: 3313

ExAC AF: 0.425 AC: 51648

Asia WGS AF: 0.602 AC: 2095 AN: 3478

EpiCase AF: 0.375

EpiControl AF: 0.375

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Sitosterolemia 1 (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.016
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.32
Sift	Benign	0.043	D
Sift4G	Uncertain	0.041	D
Polyphen		0.21	B
Vest4		0.18
MPC		0.024
ClinPred		0.033	T
GERP RS		4.1
Varity_R		0.29
gMVP		0.73
Mutation Taster		=75/25	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs4148211; hg19: chr2-44071743; COSMIC: COSV55393318;