16-16090375-C-G

Variant names:

• chr16-16090375-C-G
• rs2074087
• NM_004996.4:c.2461-30C>G

Variant summary

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

The NM_004996.4(ABCC1):​c.2461-30C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.834 in 1,551,904 control chromosomes in the GnomAD database, including 540,725 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. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.83 (51982 hom., cov: 34)
  • Exomes 𝑓: 0.83 (488743 hom.)
• Consequence: ABCC1 NM_004996.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.787
• Publications: 31 publications found

Genes affected

ABCC1 (HGNC:51): (ATP binding cassette subfamily C member 1 (ABCC1 blood group)) 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 full transporter is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions as a multispecific organic anion transporter, with oxidized glutatione, cysteinyl leukotrienes, and activated aflatoxin B1 as substrates. This protein also transports glucuronides and sulfate conjugates of steroid hormones and bile salts. Alternatively spliced variants of this gene have been described but their full-length nature is unknown. [provided by RefSeq, Apr 2012]

ABCC1 Gene-Disease associations (from GenCC):

• hearing loss, autosomal dominant 77

  Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) 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
ABCC1	NM_004996.4	c.2461-30C>G		intron_variant	Intron 18 of 30	ENST00000399410.8	NP_004987.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC1	ENST00000399410.8	c.2461-30C>G		intron_variant	Intron 18 of 30	1	NM_004996.4	ENSP00000382342.3

Frequencies

GnomAD3 genomes AF: 0.826 AC: 125640 AN: 152112 Hom.: 51954 Cov.: 34

Gnomad AFR AF: 0.819

Gnomad AMI AF: 0.908

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.823

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.842

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.846

Gnomad OTH AF: 0.801

GnomAD2 exomes AF: 0.812 AC: 166372 AN: 204952 AF XY: 0.807

Gnomad AFR exome AF: 0.816

Gnomad AMR exome AF: 0.787

Gnomad ASJ exome AF: 0.772

Gnomad EAS exome AF: 0.823

Gnomad FIN exome AF: 0.845

Gnomad NFE exome AF: 0.843

Gnomad OTH exome AF: 0.813

GnomAD4 exome AF: 0.834 AC: 1167863 AN: 1399674 Hom.: 488743 Cov.: 39 AF XY: 0.830 AC XY: 570996 AN XY: 688106

African (AFR) AF: 0.807 AC: 26081 AN: 32332

American (AMR) AF: 0.790 AC: 31556 AN: 39956

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 17379 AN: 22610

East Asian (EAS) AF: 0.788 AC: 30370 AN: 38544

South Asian (SAS) AF: 0.686 AC: 52420 AN: 76468

European-Finnish (FIN) AF: 0.844 AC: 42279 AN: 50102

Middle Eastern (MID) AF: 0.774 AC: 4177 AN: 5396

European-Non Finnish (NFE) AF: 0.851 AC: 916308 AN: 1076556

Other (OTH) AF: 0.819 AC: 47293 AN: 57710

GnomAD4 genome AF: 0.826 AC: 125717 AN: 152230 Hom.: 51982 Cov.: 34 AF XY: 0.821 AC XY: 61142 AN XY: 74430

African (AFR) AF: 0.819 AC: 34026 AN: 41548

American (AMR) AF: 0.801 AC: 12246 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 2688 AN: 3468

East Asian (EAS) AF: 0.823 AC: 4250 AN: 5166

South Asian (SAS) AF: 0.683 AC: 3295 AN: 4826

European-Finnish (FIN) AF: 0.842 AC: 8926 AN: 10598

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.846 AC: 57557 AN: 68024

Other (OTH) AF: 0.796 AC: 1679 AN: 2110

Alfa AF: 0.825 Hom.: 9589

Bravo AF: 0.823

Asia WGS AF: 0.754 AC: 2625 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.2
DANN	Benign	0.39
PhyloP100		0.79
BranchPoint Hunter		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2074087; hg19: chr16-16184232; COSMIC: COSV60697146; COSMIC: COSV60697146;