rs11887534

Variant names:

• chr2-43839108-G-C
• rs11887534
• NM_022437.3:c.55G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-43839108-G-C
• chr2-43839108-G-A

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.55G>C​(p.Asp19His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.064 in 1,551,174 control chromosomes in the GnomAD database, including 3,397 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,association (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D19E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.064 (383 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3014 hom.)
• Consequence: ABCG8 NM_022437.3 missense
• Clinical Significance: Benign/Likely benign; association criteria provided, multiple submitters, no conflicts P:1 B:13 O:2
• Conservation: PhyloP100: 1.10
• Publications: 196 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]

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]

ABCG5 Gene-Disease associations (from GenCC):

• sitosterolemia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• sitosterolemia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• sitosterolemia 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018903911).
• BP6: Variant 2-43839108-G-C is Benign according to our data. Variant chr2-43839108-G-C is described in ClinVar as Benign/Likely_benign|association. ClinVar VariationId is 4975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0659 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.55G>C	p.Asp19His	missense	Exon 1 of 13	NP_071882.1	Q9H221-1
	ABCG8	NM_001357321.2		c.55G>C	p.Asp19His	missense	Exon 1 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.55G>C	p.Asp19His	missense	Exon 1 of 13	ENSP00000272286.2	Q9H221-1
	ABCG8	ENST00000881895.1		c.55G>C	p.Asp19His	missense	Exon 1 of 13	ENSP00000551954.1
	ABCG8	ENST00000881900.1		c.55G>C	p.Asp19His	missense	Exon 1 of 13	ENSP00000551959.1

Frequencies

GnomAD3 genomes AF: 0.0644 AC: 9803 AN: 152164 Hom.: 383 Cov.: 32

Gnomad AFR AF: 0.0651

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0692

Gnomad ASJ AF: 0.0896

Gnomad EAS AF: 0.0151

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.0888

Gnomad MID AF: 0.0573

Gnomad NFE AF: 0.0641

Gnomad OTH AF: 0.0568

GnomAD2 exomes AF: 0.0669 AC: 10371 AN: 155096 AF XY: 0.0638

Gnomad AFR exome AF: 0.0638

Gnomad AMR exome AF: 0.0990

Gnomad ASJ exome AF: 0.0937

Gnomad EAS exome AF: 0.0133

Gnomad FIN exome AF: 0.0942

Gnomad NFE exome AF: 0.0659

Gnomad OTH exome AF: 0.0678

GnomAD4 exome AF: 0.0640 AC: 89470 AN: 1398892 Hom.: 3014 Cov.: 33 AF XY: 0.0626 AC XY: 43195 AN XY: 689968

African (AFR) AF: 0.0670 AC: 2115 AN: 31590

American (AMR) AF: 0.0939 AC: 3352 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.0894 AC: 2252 AN: 25178

East Asian (EAS) AF: 0.00932 AC: 333 AN: 35736

South Asian (SAS) AF: 0.0334 AC: 2642 AN: 79220

European-Finnish (FIN) AF: 0.0884 AC: 4341 AN: 49098

Middle Eastern (MID) AF: 0.0604 AC: 343 AN: 5682

European-Non Finnish (NFE) AF: 0.0652 AC: 70306 AN: 1078720

Other (OTH) AF: 0.0653 AC: 3786 AN: 57978

GnomAD4 genome AF: 0.0644 AC: 9810 AN: 152282 Hom.: 383 Cov.: 32 AF XY: 0.0641 AC XY: 4777 AN XY: 74468

African (AFR) AF: 0.0650 AC: 2704 AN: 41572

American (AMR) AF: 0.0694 AC: 1061 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0896 AC: 311 AN: 3470

East Asian (EAS) AF: 0.0151 AC: 78 AN: 5162

South Asian (SAS) AF: 0.0356 AC: 172 AN: 4830

European-Finnish (FIN) AF: 0.0888 AC: 943 AN: 10622

Middle Eastern (MID) AF: 0.0548 AC: 16 AN: 292

European-Non Finnish (NFE) AF: 0.0641 AC: 4362 AN: 68010

Other (OTH) AF: 0.0562 AC: 119 AN: 2116

Alfa AF: 0.0653 Hom.: 248

Bravo AF: 0.0663

TwinsUK AF: 0.0696 AC: 258

ALSPAC AF: 0.0558 AC: 215

ESP6500AA AF: 0.0519 AC: 196

ESP6500EA AF: 0.0554 AC: 402

ExAC AF: 0.0307 AC: 1568

Asia WGS AF: 0.0380 AC: 131 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign; association

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (3)
-	-	2	Sitosterolemia (2)
-	-	1	ABCG8-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
1	-	-	Gallbladder disease 4 (1)
-	-	1	Sitosterolemia 1 (1)
-	-	1	Sitosterolemia 2 (1)
-	-	-	Gallstones (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.36
Sift	Benign	0.045	D
Sift4G	Uncertain	0.022	D
Polyphen		0.77	P
Vest4		0.15
MPC		0.057
ClinPred		0.035	T
GERP RS		3.6
PromoterAI		0.094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.11
gMVP		0.50
Mutation Taster		=96/4	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: rs11887534; hg19: chr2-44066247; COSMIC: COSV53211629; COSMIC: COSV53211629;