16-16046021-A-G

Variant names:

• chr16-16046021-A-G
• rs35588
• NM_004996.4:c.1218+8A>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.1218+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 1,612,758 control chromosomes in the GnomAD database, including 85,821 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.40 (13561 hom., cov: 32)
  • Exomes 𝑓: 0.31 (72260 hom.)
• Consequence: ABCC1 NM_004996.4 splice_region, intron
• Scores: Splicing: ADA: 0.000007049
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 16 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):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
• hearing loss, autosomal dominant 77

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004996.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC1	NM_004996.4	MANE Select	c.1218+8A>G		splice_region intron	N/A	NP_004987.2	P33527-1
	ABCC1	NM_019901.2		c.1092+8A>G		splice_region intron	N/A	NP_063956.2
	ABCC1	NM_019902.2		c.1218+8A>G		splice_region intron	N/A	NP_063957.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC1	ENST00000399410.8	TSL:1 MANE Select	c.1218+8A>G		splice_region intron	N/A	ENSP00000382342.3	P33527-1
	ABCC1	ENST00000572882.3	TSL:1	c.1218+8A>G		splice_region intron	N/A	ENSP00000461615.2	P33527-2
	ABCC1	ENST00000574224.2	TSL:1	n.1293+8A>G		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60316 AN: 151862 Hom.: 13533 Cov.: 32

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.368

GnomAD2 exomes AF: 0.328 AC: 81188 AN: 247250 AF XY: 0.316

Gnomad AFR exome AF: 0.632

Gnomad AMR exome AF: 0.346

Gnomad ASJ exome AF: 0.314

Gnomad EAS exome AF: 0.426

Gnomad FIN exome AF: 0.334

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.307 AC: 448891 AN: 1460780 Hom.: 72260 Cov.: 37 AF XY: 0.303 AC XY: 220171 AN XY: 726608

African (AFR) AF: 0.631 AC: 21121 AN: 33456

American (AMR) AF: 0.345 AC: 15367 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 8393 AN: 26128

East Asian (EAS) AF: 0.415 AC: 16441 AN: 39648

South Asian (SAS) AF: 0.206 AC: 17721 AN: 86168

European-Finnish (FIN) AF: 0.341 AC: 18125 AN: 53230

Middle Eastern (MID) AF: 0.315 AC: 1816 AN: 5756

European-Non Finnish (NFE) AF: 0.298 AC: 330912 AN: 1111436

Other (OTH) AF: 0.315 AC: 18995 AN: 60364

GnomAD4 genome AF: 0.397 AC: 60395 AN: 151978 Hom.: 13561 Cov.: 32 AF XY: 0.396 AC XY: 29433 AN XY: 74270

African (AFR) AF: 0.621 AC: 25737 AN: 41456

American (AMR) AF: 0.335 AC: 5120 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1096 AN: 3462

East Asian (EAS) AF: 0.424 AC: 2181 AN: 5142

South Asian (SAS) AF: 0.199 AC: 957 AN: 4818

European-Finnish (FIN) AF: 0.338 AC: 3568 AN: 10560

Middle Eastern (MID) AF: 0.377 AC: 110 AN: 292

European-Non Finnish (NFE) AF: 0.299 AC: 20318 AN: 67954

Other (OTH) AF: 0.365 AC: 771 AN: 2110

Alfa AF: 0.352 Hom.: 4833

Bravo AF: 0.413

Asia WGS AF: 0.329 AC: 1143 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.32
DANN	Benign	0.53
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000070
dbscSNV1_RF	Benign	0.0
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: rs35588; hg19: chr16-16139878; COSMIC: COSV60697192;