rs2230028

Variant names:

• chr7-87426860-T-C
• rs2230028
• NM_000443.4:c.1954A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-87426860-T-C
• chr7-87426860-T-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000443.4(ABCB4):​c.1954A>G​(p.Arg652Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0895 in 1,613,710 control chromosomes in the GnomAD database, including 9,653 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2931 hom., cov: 32)
  • Exomes 𝑓: 0.083 (6722 hom.)
• Consequence: ABCB4 NM_000443.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.941
• Publications: 52 publications found

Genes affected

ABCB4 (HGNC:45): (ATP binding cassette subfamily B member 4) The membrane-associated 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 MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance as well as antigen presentation. This gene encodes a full transporter and member of the p-glycoprotein family of membrane proteins with phosphatidylcholine as its substrate. The function of this protein has not yet been determined; however, it may involve transport of phospholipids from liver hepatocytes into bile. Alternative splicing of this gene results in several products of undetermined function. [provided by RefSeq, Jul 2008]

ABCB4 Gene-Disease associations (from GenCC):

• progressive familial intrahepatic cholestasis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• gallbladder disease 1

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the ABCB4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 1.9749 (below the threshold of 3.09). Trascript score misZ: 3.5425 (above the threshold of 3.09). GenCC associations: The gene is linked to pancreatitis, gallbladder disease 1, progressive familial intrahepatic cholestasis type 3.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0030877888).
• BP6: Variant 7-87426860-T-C is Benign according to our data. Variant chr7-87426860-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000443.4. 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
	ABCB4	NM_000443.4	MANE Select	c.1954A>G	p.Arg652Gly	missense	Exon 16 of 28	NP_000434.1	P21439-2
	ABCB4	NM_018849.3		c.1954A>G	p.Arg652Gly	missense	Exon 16 of 28	NP_061337.1	P21439-1
	ABCB4	NM_018850.3		c.1954A>G	p.Arg652Gly	missense	Exon 16 of 27	NP_061338.1	P21439-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB4	ENST00000649586.2	MANE Select	c.1954A>G	p.Arg652Gly	missense	Exon 16 of 28	ENSP00000496956.2	P21439-2
	ABCB4	ENST00000265723.8	TSL:1	c.1954A>G	p.Arg652Gly	missense	Exon 16 of 28	ENSP00000265723.4	P21439-1
	ABCB4	ENST00000359206.8	TSL:1	c.1954A>G	p.Arg652Gly	missense	Exon 16 of 28	ENSP00000352135.3	P21439-2

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23204 AN: 151950 Hom.: 2907 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0958

Gnomad ASJ AF: 0.0950

Gnomad EAS AF: 0.0269

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.0737

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0767

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.0998 AC: 25065 AN: 251072 AF XY: 0.0968

Gnomad AFR exome AF: 0.354

Gnomad AMR exome AF: 0.0899

Gnomad ASJ exome AF: 0.0900

Gnomad EAS exome AF: 0.0266

Gnomad FIN exome AF: 0.0725

Gnomad NFE exome AF: 0.0737

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.0829 AC: 121131 AN: 1461642 Hom.: 6722 Cov.: 33 AF XY: 0.0837 AC XY: 60883 AN XY: 727104

African (AFR) AF: 0.355 AC: 11894 AN: 33468

American (AMR) AF: 0.0914 AC: 4089 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0917 AC: 2397 AN: 26130

East Asian (EAS) AF: 0.0225 AC: 893 AN: 39674

South Asian (SAS) AF: 0.136 AC: 11711 AN: 86246

European-Finnish (FIN) AF: 0.0736 AC: 3930 AN: 53386

Middle Eastern (MID) AF: 0.0794 AC: 458 AN: 5768

European-Non Finnish (NFE) AF: 0.0720 AC: 80045 AN: 1111870

Other (OTH) AF: 0.0946 AC: 5714 AN: 60382

GnomAD4 genome AF: 0.153 AC: 23279 AN: 152068 Hom.: 2931 Cov.: 32 AF XY: 0.151 AC XY: 11232 AN XY: 74356

African (AFR) AF: 0.345 AC: 14303 AN: 41408

American (AMR) AF: 0.0957 AC: 1463 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0950 AC: 330 AN: 3472

East Asian (EAS) AF: 0.0268 AC: 139 AN: 5184

South Asian (SAS) AF: 0.137 AC: 659 AN: 4824

European-Finnish (FIN) AF: 0.0737 AC: 781 AN: 10592

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0767 AC: 5213 AN: 67992

Other (OTH) AF: 0.130 AC: 275 AN: 2108

Alfa AF: 0.0990 Hom.: 4754

Bravo AF: 0.160

TwinsUK AF: 0.0782 AC: 290

ALSPAC AF: 0.0703 AC: 271

ESP6500AA AF: 0.343 AC: 1513

ESP6500EA AF: 0.0790 AC: 679

ExAC AF: 0.105 AC: 12793

Asia WGS AF: 0.100 AC: 346 AN: 3478

EpiCase AF: 0.0781

EpiControl AF: 0.0745

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	2	Progressive familial intrahepatic cholestasis type 3 (2)
-	-	1	Cholestasis, intrahepatic, of pregnancy, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.6
DANN	Benign	0.44
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00063	N
LIST_S2	Benign	0.047	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.31	N
PhyloP100		0.94
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.23
Sift	Benign	0.34	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.020
MPC		0.35
ClinPred		0.00072	T
GERP RS		1.1
Varity_R		0.039
gMVP		0.31
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: rs2230028; hg19: chr7-87056176; COSMIC: COSV55939739;