chr3-183967746-A-G

Variant names:

• chr3-183967746-A-G
• rs939336
• NM_005688.4:c.1782T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005688.4(ABCC5):​c.1782T>C​(p.Cys594Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 1,611,950 control chromosomes in the GnomAD database, including 267,442 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30499 hom., cov: 32)
  • Exomes 𝑓: 0.57 (236943 hom.)
• Consequence: ABCC5 NM_005688.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.150
• Publications: 53 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 3-183967746-A-G is Benign according to our data. Variant chr3-183967746-A-G is described in ClinVar as Benign. ClinVar VariationId is 1252281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC5	NM_005688.4	c.1782T>C	p.Cys594Cys	synonymous_variant	Exon 12 of 30	ENST00000334444.11	NP_005679.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC5	ENST00000334444.11	c.1782T>C	p.Cys594Cys	synonymous_variant	Exon 12 of 30	1	NM_005688.4	ENSP00000333926.6

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94823 AN: 151996 Hom.: 30455 Cov.: 32

Gnomad AFR AF: 0.766

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.860

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.631

GnomAD2 exomes AF: 0.582 AC: 145318 AN: 249500 AF XY: 0.576

Gnomad AFR exome AF: 0.780

Gnomad AMR exome AF: 0.524

Gnomad ASJ exome AF: 0.550

Gnomad EAS exome AF: 0.859

Gnomad FIN exome AF: 0.502

Gnomad NFE exome AF: 0.556

Gnomad OTH exome AF: 0.582

GnomAD4 exome AF: 0.566 AC: 825669 AN: 1459836 Hom.: 236943 Cov.: 40 AF XY: 0.564 AC XY: 409949 AN XY: 726342

African (AFR) AF: 0.774 AC: 25880 AN: 33434

American (AMR) AF: 0.531 AC: 23725 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 14421 AN: 26112

East Asian (EAS) AF: 0.864 AC: 34296 AN: 39674

South Asian (SAS) AF: 0.546 AC: 47066 AN: 86206

European-Finnish (FIN) AF: 0.510 AC: 27199 AN: 53372

Middle Eastern (MID) AF: 0.586 AC: 3378 AN: 5760

European-Non Finnish (NFE) AF: 0.554 AC: 614895 AN: 1110260

Other (OTH) AF: 0.577 AC: 34809 AN: 60316

GnomAD4 genome AF: 0.624 AC: 94919 AN: 152114 Hom.: 30499 Cov.: 32 AF XY: 0.618 AC XY: 45943 AN XY: 74334

African (AFR) AF: 0.766 AC: 31787 AN: 41494

American (AMR) AF: 0.583 AC: 8912 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1912 AN: 3470

East Asian (EAS) AF: 0.861 AC: 4457 AN: 5176

South Asian (SAS) AF: 0.561 AC: 2707 AN: 4824

European-Finnish (FIN) AF: 0.501 AC: 5291 AN: 10570

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.558 AC: 37917 AN: 67984

Other (OTH) AF: 0.637 AC: 1347 AN: 2114

Alfa AF: 0.584 Hom.: 97772

Bravo AF: 0.636

Asia WGS AF: 0.730 AC: 2539 AN: 3478

EpiCase AF: 0.564

EpiControl AF: 0.577

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 27, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.2
DANN	Benign	0.52
PhyloP100		0.15
Mutation Taster		=78/22	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: rs939336; hg19: chr3-183685534; COSMIC: COSV55588306;