rs2292998

Positions:

• chr3-183946045-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005688.4(ABCC5):​c.3415-106A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.579 in 988,376 control chromosomes in the GnomAD database, including 170,278 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.63 (31046 hom., cov: 32)
  • Exomes 𝑓: 0.57 (139232 hom.)
• Consequence: ABCC5 NM_005688.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.09

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.831 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC5	NM_005688.4	c.3415-106A>G		intron_variant		ENST00000334444.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC5	ENST00000334444.11	c.3415-106A>G		intron_variant		1	NM_005688.4	P1
ABCC5	ENST00000265586.10	c.3286-106A>G		intron_variant		5
ABCC5	ENST00000437205.5	c.*2108-106A>G		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.629 AC: 95536 AN: 151974 Hom.: 30997 Cov.: 32

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.585

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.635

GnomAD4 exome AF: 0.570 AC: 476410 AN: 836284 Hom.: 139232 AF XY: 0.569 AC XY: 249735 AN XY: 439260

Gnomad4 AFR exome AF: 0.789

Gnomad4 AMR exome AF: 0.531

Gnomad4 ASJ exome AF: 0.552

Gnomad4 EAS exome AF: 0.853

Gnomad4 SAS exome AF: 0.547

Gnomad4 FIN exome AF: 0.509

Gnomad4 NFE exome AF: 0.553

Gnomad4 OTH exome AF: 0.578

GnomAD4 genome AF: 0.629 AC: 95636 AN: 152092 Hom.: 31046 Cov.: 32 AF XY: 0.623 AC XY: 46292 AN XY: 74336

Gnomad4 AFR AF: 0.783

Gnomad4 AMR AF: 0.586

Gnomad4 ASJ AF: 0.552

Gnomad4 EAS AF: 0.852

Gnomad4 SAS AF: 0.561

Gnomad4 FIN AF: 0.501

Gnomad4 NFE AF: 0.558

Gnomad4 OTH AF: 0.640

Alfa AF: 0.564 Hom.: 23283

Bravo AF: 0.642

Asia WGS AF: 0.729 AC: 2535 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.0050
DANN	Benign	0.32

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: rs2292998; hg19: chr3-183663833; COSMIC: COSV55588287; COSMIC: COSV55588287;