rs4148356

Positions:

• chr16-16083418-G-A

Variant summary

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

The ENST00000399410.8(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. 14/20 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 ENST00000399410.8 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.176

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC1	NM_004996.4	c.2168G>A	p.Arg723Gln	missense_variant	17/31	ENST00000399410.8	NP_004987.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC1	ENST00000399410.8	c.2168G>A	p.Arg723Gln	missense_variant	17/31	1	NM_004996.4	ENSP00000382342	P1

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

GnomAD3 exomes AF: 0.0235 AC: 5860 AN: 249542 Hom.: 164 AF XY: 0.0209 AC XY: 2828 AN XY: 135392

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 SAS exome AF: 0.00716

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

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.0743

Gnomad4 ASJ exome AF: 0.00945

Gnomad4 EAS exome AF: 0.0614

Gnomad4 SAS exome AF: 0.00848

Gnomad4 FIN exome AF: 0.0198

Gnomad4 NFE exome AF: 0.0110

Gnomad4 OTH exome AF: 0.0132

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

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.0388

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.0504

Gnomad4 SAS AF: 0.00954

Gnomad4 FIN AF: 0.0229

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0128 Hom.: 59

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial cancer of breast Uncertain:1

Uncertain significance, no assertion criteria provided

research

Research Lab, National Institute of Public Health

Feb 01, 2014

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Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.85	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.36	N;.
REVEL	Uncertain	0.29
Sift	Benign	0.82	T;.
Sift4G	Benign	0.56	T;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

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: rs4148356; hg19: chr16-16177275; COSMIC: COSV60694944;