rs60782127

Positions:

• chr16-16048222-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000399410.8(ABCC1):​c.1299G>T​(p.Arg433Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,614,196 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0075 (8 hom., cov: 32)
  • Exomes 𝑓: 0.012 (131 hom.)
• Consequence: ABCC1 ENST00000399410.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.0320

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019949764).
• BP6: Variant 16-16048222-G-T is Benign according to our data. Variant chr16-16048222-G-T is described in ClinVar as [Benign]. Clinvar id is 489391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1149 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC1	NM_004996.4	c.1299G>T	p.Arg433Ser	missense_variant	10/31	ENST00000399410.8	NP_004987.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC1	ENST00000399410.8	c.1299G>T	p.Arg433Ser	missense_variant	10/31	1	NM_004996.4	ENSP00000382342	P1

Frequencies

GnomAD3 genomes AF: 0.00755 AC: 1149 AN: 152192 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00890 AC: 2221 AN: 249556 Hom.: 14 AF XY: 0.00862 AC XY: 1167 AN XY: 135394

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00417

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00278

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.00858

GnomAD4 exome AF: 0.0117 AC: 17119 AN: 1461886 Hom.: 131 Cov.: 32 AF XY: 0.0114 AC XY: 8269 AN XY: 727244

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00436

Gnomad4 ASJ exome AF: 0.0129

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00260

Gnomad4 FIN exome AF: 0.0111

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.00988

GnomAD4 genome AF: 0.00754 AC: 1149 AN: 152310 Hom.: 8 Cov.: 32 AF XY: 0.00681 AC XY: 507 AN XY: 74478

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00942

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.0117 Hom.: 16

Bravo AF: 0.00691

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00168 AC: 7

ESP6500EA AF: 0.0122 AC: 103

ExAC AF: 0.00937 AC: 1134

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0119

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ABCC1: BS1, BS2 -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Benign	0.020	T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.1	D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.29		Loss of catalytic residue at R433 (P = 0.1193);.;
MVP		0.93
MPC		1.1
ClinPred		0.044	T
GERP RS		-0.26
Varity_R		0.86
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs60782127; hg19: chr16-16142079; COSMIC: COSV104658482;