rs6756629

Variant names:

• chr2-43837951-G-A
• rs6756629
• NM_022436.3:c.148C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-43837951-G-A
• chr2-43837951-G-C
• chr2-43837951-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022436.3(ABCG5):​c.148C>T​(p.Arg50Cys) variant causes a missense change. The variant allele was found at a frequency of 0.063 in 1,613,816 control chromosomes in the GnomAD database, including 3,457 homozygotes. In-silico tool predicts 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. R50L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.068 (425 hom., cov: 32)
  • Exomes 𝑓: 0.063 (3032 hom.)
• Consequence: ABCG5 NM_022436.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.29
• Publications: 111 publications found

Genes affected

ABCG5 (HGNC:13886): (ATP binding cassette subfamily G member 5) 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 as a half-transporter to limit intestinal absorption and promote biliary excretion of sterols. It is expressed in a tissue-specific manner in the liver, colon, and intestine. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG8. Mutations in this gene may contribute to sterol accumulation and atheroschlerosis, and have been observed in patients with sitosterolemia. [provided by RefSeq, Jul 2008]

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=0.0029157996).
• BP6: Variant 2-43837951-G-A is Benign according to our data. Variant chr2-43837951-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 286793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0772 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022436.3. 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
	ABCG5	NM_022436.3	MANE Select	c.148C>T	p.Arg50Cys	missense	Exon 2 of 13	NP_071881.1	Q9H222-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG5	ENST00000405322.8	TSL:1 MANE Select	c.148C>T	p.Arg50Cys	missense	Exon 2 of 13	ENSP00000384513.2	Q9H222-1
	ABCG5	ENST00000486512.5	TSL:1	n.800C>T		non_coding_transcript_exon	Exon 1 of 9
	ABCG5	ENST00000882115.1		c.148C>T	p.Arg50Cys	missense	Exon 2 of 13	ENSP00000552174.1

Frequencies

GnomAD3 genomes AF: 0.0676 AC: 10274 AN: 152086 Hom.: 425 Cov.: 32

Gnomad AFR AF: 0.0795

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.0706

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.0359

Gnomad FIN AF: 0.0877

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0623

Gnomad OTH AF: 0.0583

GnomAD2 exomes AF: 0.0667 AC: 16775 AN: 251368 AF XY: 0.0639

Gnomad AFR exome AF: 0.0782

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.0929

Gnomad EAS exome AF: 0.0138

Gnomad FIN exome AF: 0.0909

Gnomad NFE exome AF: 0.0640

Gnomad OTH exome AF: 0.0688

GnomAD4 exome AF: 0.0625 AC: 91412 AN: 1461612 Hom.: 3032 Cov.: 31 AF XY: 0.0611 AC XY: 44459 AN XY: 727118

African (AFR) AF: 0.0823 AC: 2756 AN: 33478

American (AMR) AF: 0.0988 AC: 4418 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0876 AC: 2288 AN: 26128

East Asian (EAS) AF: 0.00962 AC: 382 AN: 39698

South Asian (SAS) AF: 0.0334 AC: 2881 AN: 86250

European-Finnish (FIN) AF: 0.0865 AC: 4617 AN: 53374

Middle Eastern (MID) AF: 0.0604 AC: 348 AN: 5766

European-Non Finnish (NFE) AF: 0.0628 AC: 69786 AN: 1111836

Other (OTH) AF: 0.0652 AC: 3936 AN: 60366

GnomAD4 genome AF: 0.0676 AC: 10286 AN: 152204 Hom.: 425 Cov.: 32 AF XY: 0.0672 AC XY: 4998 AN XY: 74428

African (AFR) AF: 0.0795 AC: 3302 AN: 41540

American (AMR) AF: 0.0708 AC: 1082 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0888 AC: 308 AN: 3468

East Asian (EAS) AF: 0.0149 AC: 77 AN: 5182

South Asian (SAS) AF: 0.0359 AC: 173 AN: 4820

European-Finnish (FIN) AF: 0.0877 AC: 929 AN: 10598

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0623 AC: 4239 AN: 67988

Other (OTH) AF: 0.0577 AC: 122 AN: 2114

Alfa AF: 0.0661 Hom.: 1242

Bravo AF: 0.0700

TwinsUK AF: 0.0663 AC: 246

ALSPAC AF: 0.0535 AC: 206

ESP6500AA AF: 0.0724 AC: 319

ESP6500EA AF: 0.0637 AC: 548

ExAC AF: 0.0643 AC: 7806

Asia WGS AF: 0.0400 AC: 137 AN: 3478

EpiCase AF: 0.0666

EpiControl AF: 0.0659

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Sitosterolemia (2)
-	-	1	ABCG5-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Sitosterolemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	0.14
Eigen_PC	Benign	-0.0074
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.3
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.14
MPC		0.098
ClinPred		0.025	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.13
gMVP		0.70
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6756629; hg19: chr2-44065090; COSMIC: COSV53211625; COSMIC: COSV53211625;