rs4148356

Variant names:

• chr16-16083418-G-A
• rs4148356
• NM_004996.4:c.2168G>A

Variant summary

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

The NM_004996.4(ABCC1):​c.2168G>A​(p.Arg723Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,613,812 control chromosomes in the GnomAD database, including 404 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R723G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (36 hom., cov: 33)
  • Exomes 𝑓: 0.014 (368 hom.)
• Consequence: ABCC1 NM_004996.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.176
• Publications: 49 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 (MetaRNN=0.0024918914).
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0722 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.2168G>A	p.Arg723Gln	missense	Exon 17 of 31	NP_004987.2	P33527-1
	ABCC1	NM_019901.2		c.2042G>A	p.Arg681Gln	missense	Exon 16 of 30	NP_063956.2
	ABCC1	NM_019902.2		c.2021G>A	p.Arg674Gln	missense	Exon 16 of 30	NP_063957.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC1	ENST00000399410.8	TSL:1 MANE Select	c.2168G>A	p.Arg723Gln	missense	Exon 17 of 31	ENSP00000382342.3	P33527-1
	ABCC1	ENST00000572882.3	TSL:1	c.2116-3406G>A		intron	N/A	ENSP00000461615.2	P33527-2
	ABCC1	ENST00000914156.1		c.2324G>A	p.Arg775Gln	missense	Exon 18 of 32	ENSP00000584215.1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2039 AN: 152130 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.0503

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.0229

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0235 AC: 5860 AN: 249542 AF XY: 0.0209

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.0789

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.0480

Gnomad FIN exome AF: 0.0206

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.0172

GnomAD4 exome AF: 0.0144 AC: 20975 AN: 1461562 Hom.: 368 Cov.: 31 AF XY: 0.0140 AC XY: 10164 AN XY: 727078

African (AFR) AF: 0.00206 AC: 69 AN: 33470

American (AMR) AF: 0.0743 AC: 3323 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00945 AC: 247 AN: 26136

East Asian (EAS) AF: 0.0614 AC: 2439 AN: 39700

South Asian (SAS) AF: 0.00848 AC: 731 AN: 86230

European-Finnish (FIN) AF: 0.0198 AC: 1059 AN: 53420

Middle Eastern (MID) AF: 0.00471 AC: 26 AN: 5516

European-Non Finnish (NFE) AF: 0.0110 AC: 12284 AN: 1111998

Other (OTH) AF: 0.0132 AC: 797 AN: 60368

GnomAD4 genome AF: 0.0134 AC: 2043 AN: 152250 Hom.: 36 Cov.: 33 AF XY: 0.0144 AC XY: 1069 AN XY: 74444

African (AFR) AF: 0.00279 AC: 116 AN: 41546

American (AMR) AF: 0.0388 AC: 593 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.0504 AC: 261 AN: 5182

South Asian (SAS) AF: 0.00954 AC: 46 AN: 4824

European-Finnish (FIN) AF: 0.0229 AC: 243 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0106 AC: 721 AN: 68016

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.0134 Hom.: 137

Bravo AF: 0.0151

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00346 AC: 14

ESP6500EA AF: 0.0120 AC: 101

ExAC AF: 0.0210 AC: 2547

Asia WGS AF: 0.0380 AC: 131 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.00895

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.79
DEOGEN2	Benign	0.40	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.18
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.36	N
REVEL	Uncertain	0.29
Sift	Benign	0.82	T
Sift4G	Benign	0.56	T
Polyphen		0.014	B
Vest4		0.092
MPC		0.39
ClinPred		0.0044	T
GERP RS		-2.9
Varity_R		0.070
gMVP		0.39
Mutation Taster		=98/2	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: rs4148356; hg19: chr16-16177275; COSMIC: COSV60694944;