chr7-87600124-T-G

Position:

• chr7-87600124-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001348946.2(ABCB1):​c.61A>C​(p.Asn21His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N21D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCB1 NM_001348946.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.196

Genes affected

ABCB1 (HGNC:40): (ATP binding cassette subfamily B member 1) 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. The protein encoded by this gene is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs. This protein also functions as a transporter in the blood-brain barrier. Mutations in this gene are associated with colchicine resistance and Inflammatory bowel disease 13. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0645307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB1	NM_001348946.2	c.61A>C	p.Asn21His	missense_variant	2/28	ENST00000622132.5	NP_001335875.1
ABCB1	NM_001348945.2	c.271A>C	p.Asn91His	missense_variant	6/32		NP_001335874.1
ABCB1	NM_000927.5	c.61A>C	p.Asn21His	missense_variant	3/29		NP_000918.2
ABCB1	NM_001348944.2	c.61A>C	p.Asn21His	missense_variant	4/30		NP_001335873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5	c.61A>C	p.Asn21His	missense_variant	2/28	1	NM_001348946.2	ENSP00000478255	P1
ABCB1	ENST00000265724.8	c.61A>C	p.Asn21His	missense_variant	3/29	1		ENSP00000265724	P1
ABCB1	ENST00000543898.5	c.61A>C	p.Asn21His	missense_variant	3/28	5		ENSP00000444095
ABCB1	ENST00000416177.1	c.61A>C	p.Asn21His	missense_variant	4/6	5		ENSP00000399419

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	1.3
DANN	Benign	0.36
DEOGEN2	Benign	0.052	.;.;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.33	T;.;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.065	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N;N;N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	.;N;N;D
REVEL	Benign	0.23
Sift	Benign	0.096	.;T;T;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.14
MutPred		0.17		Loss of methylation at K25 (P = 0.1033);Loss of methylation at K25 (P = 0.1033);Loss of methylation at K25 (P = 0.1033);Loss of methylation at K25 (P = 0.1033);
MVP		0.70
MPC		0.29
ClinPred		0.035	T
GERP RS		-2.7
Varity_R		0.046
gMVP		0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs9282564; hg19: chr7-87229440;