3-183961744-A-G

Variant names:

• chr3-183961744-A-G
• rs6443924
• NM_005688.4:c.2236-90T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005688.4(ABCC5):​c.2236-90T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 1,482,902 control chromosomes in the GnomAD database, including 248,145 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 0.62 (30497 hom., cov: 32)
  • Exomes 𝑓: 0.57 (217648 hom.)
• Consequence: ABCC5 NM_005688.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.306
• Publications: 19 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005688.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC5	NM_005688.4	MANE Select	c.2236-90T>C		intron	N/A	NP_005679.2
	ABCC5	NM_001320032.2		c.820-90T>C		intron	N/A	NP_001306961.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC5	ENST00000334444.11	TSL:1 MANE Select	c.2236-90T>C		intron	N/A	ENSP00000333926.6
	ABCC5	ENST00000265586.10	TSL:5	c.2236-90T>C		intron	N/A	ENSP00000265586.6
	ABCC5	ENST00000437205.5	TSL:5	n.*929-90T>C		intron	N/A	ENSP00000403510.1

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94821 AN: 151980 Hom.: 30453 Cov.: 32

Gnomad AFR AF: 0.766

Gnomad AMI AF: 0.458

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: 0.595

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.631

GnomAD4 exome AF: 0.567 AC: 754747 AN: 1330804 Hom.: 217648 AF XY: 0.566 AC XY: 373741 AN XY: 660386

African (AFR) AF: 0.776 AC: 22972 AN: 29620

American (AMR) AF: 0.533 AC: 19020 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 12275 AN: 22144

East Asian (EAS) AF: 0.865 AC: 33140 AN: 38294

South Asian (SAS) AF: 0.546 AC: 39688 AN: 72688

European-Finnish (FIN) AF: 0.509 AC: 21516 AN: 42266

Middle Eastern (MID) AF: 0.583 AC: 3116 AN: 5346

European-Non Finnish (NFE) AF: 0.555 AC: 570979 AN: 1029200

Other (OTH) AF: 0.577 AC: 32041 AN: 55552

GnomAD4 genome AF: 0.624 AC: 94917 AN: 152098 Hom.: 30497 Cov.: 32 AF XY: 0.618 AC XY: 45972 AN XY: 74364

African (AFR) AF: 0.766 AC: 31789 AN: 41502

American (AMR) AF: 0.583 AC: 8915 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1911 AN: 3468

East Asian (EAS) AF: 0.861 AC: 4458 AN: 5176

South Asian (SAS) AF: 0.561 AC: 2706 AN: 4822

European-Finnish (FIN) AF: 0.501 AC: 5299 AN: 10570

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.558 AC: 37899 AN: 67954

Other (OTH) AF: 0.637 AC: 1348 AN: 2116

Alfa AF: 0.580 Hom.: 33020

Bravo AF: 0.636

Asia WGS AF: 0.730 AC: 2540 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.7
DANN	Benign	0.61
PhyloP100		0.31
Mutation Taster		=100/0	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: rs6443924; hg19: chr3-183679532; COSMIC: COSV55588298;