Genetic Variant ABCC5:p.Val1118Leu (chr3-183947386-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005688.4(ABCC5):c.3352G>C(p.Val1118Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. V1118F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ABCC5
NM_005688.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.89

Variant links:

Genes affected

ABCC5 (HGNC:56): (ATP binding cassette subfamily C 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 MRP subfamily which is involved in multi-drug resistance. This protein functions in the cellular export of its substrate, cyclic nucleotides. This export contributes to the degradation of phosphodiesterases and possibly an elimination pathway for cyclic nucleotides. Studies show that this protein provides resistance to thiopurine anticancer drugs, 6-mercatopurine and thioguanine, and the anti-HIV drug 9-(2-phosphonylmethoxyethyl)adenine. This protein may be involved in resistance to thiopurines in acute lymphoblastic leukemia and antiretroviral nucleoside analogs in HIV-infected patients. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ABCC5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC5	NM_005688.4 link	c.3352G>C	p.Val1118Leu	missense_variant	Exon 23 of 30	ENST00000334444.11	NP_005679.2	O15440-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCC5	ENST00000334444.11 link	c.3352G>C	p.Val1118Leu	missense_variant	Exon 23 of 30	1	NM_005688.4	ENSP00000333926.6	O15440-1
ABCC5	ENST00000265586.10 link	c.3223G>C	p.Val1075Leu	missense_variant	Exon 22 of 29	5		ENSP00000265586.6	O15440-5
ABCC5	ENST00000437205.5 link	n.*2045G>C		non_coding_transcript_exon_variant	Exon 23 of 30	5		ENSP00000403510.1	F8WCY8
ABCC5	ENST00000437205.5 link	n.*2045G>C		3_prime_UTR_variant	Exon 23 of 30	5		ENSP00000403510.1	F8WCY8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.68

D;D

MetaSVM

Uncertain

0.0028

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

7.9

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.3

N;N

REVEL

Uncertain

0.55

Sift

Benign

0.033

D;D

Sift4G

Uncertain

0.027

D;D

Polyphen

0.81

P;.

Vest4

0.84

MutPred

0.42

Gain of helix (P = 0.132);.;

MVP

0.61

MPC

1.3

ClinPred

0.94

GERP RS

5.6

Varity_R

0.50

gMVP

0.93

Mutation Taster

=49/51

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over