7-87566218-C-G

Variant names:

• chr7-87566218-C-G
• rs1128501
• NM_001348946.2:c.554G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001348946.2(ABCB1):​c.554G>C​(p.Gly185Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G185V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCB1 NM_001348946.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.54
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-87566218-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13698.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB1	NM_001348946.2	c.554G>C	p.Gly185Ala	missense_variant	Exon 7 of 28	ENST00000622132.5	NP_001335875.1
ABCB1	NM_001348945.2	c.764G>C	p.Gly255Ala	missense_variant	Exon 11 of 32		NP_001335874.1
ABCB1	NM_000927.5	c.554G>C	p.Gly185Ala	missense_variant	Exon 8 of 29		NP_000918.2
ABCB1	NM_001348944.2	c.554G>C	p.Gly185Ala	missense_variant	Exon 9 of 30		NP_001335873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB1	ENST00000622132.5	c.554G>C	p.Gly185Ala	missense_variant	Exon 7 of 28	1	NM_001348946.2	ENSP00000478255.1
ABCB1	ENST00000265724.8	c.554G>C	p.Gly185Ala	missense_variant	Exon 8 of 29	1		ENSP00000265724.3
ABCB1	ENST00000543898.5	c.362G>C	p.Gly121Ala	missense_variant	Exon 7 of 28	5		ENSP00000444095.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.1	M;M;.
PhyloP100		7.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.0	.;D;D
Sift	Pathogenic	0.0	.;T;T
Sift4G	Benign	0.38	T;T;T
Vest4		0.89
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.87
gMVP		0.88
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1128501; hg19: chr7-87195534;