rs113646094

chr10-99804255-C-Gchr10-99804255-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000392.5(ABCC2):c.1446C>G(p.Thr482=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,613,976 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T482T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (20 hom., cov: 32)
  • Exomes 𝑓: 0.011 (131 hom.)
• Consequence: ABCC2 NM_000392.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.293

Genes affected

ABCC2 (HGNC:53): (ATP binding cassette subfamily C member 2) 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 protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein is expressed in the canalicular (apical) part of the hepatocyte and functions in biliary transport. Substrates include anticancer drugs such as vinblastine; therefore, this protein appears to contribute to drug resistance in mammalian cells. Several different mutations in this gene have been observed in patients with Dubin-Johnson syndrome (DJS), an autosomal recessive disorder characterized by conjugated hyperbilirubinemia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 10-99804255-C-G is Benign according to our data. Variant chr10-99804255-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 255993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-99804255-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.293 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.011 (1681/152156) while in subpopulation NFE AF= 0.0148 (1009/67994). AF 95% confidence interval is 0.0141. There are 20 homozygotes in gnomad4. There are 891 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC2	NM_000392.5	c.1446C>G	p.Thr482=	synonymous_variant	10/32	ENST00000647814.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC2	ENST00000647814.1	c.1446C>G	p.Thr482=	synonymous_variant	10/32		NM_000392.5	P1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1681 AN: 152038 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0359

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0102 AC: 2567 AN: 251050 Hom.: 18 AF XY: 0.0102 AC XY: 1390 AN XY: 135650

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.0304

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.00718

GnomAD4 exome AF: 0.0115 AC: 16739 AN: 1461820 Hom.: 131 Cov.: 32 AF XY: 0.0112 AC XY: 8136 AN XY: 727208

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00326

Gnomad4 ASJ exome AF: 0.0120

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00297

Gnomad4 FIN exome AF: 0.0280

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.00896

GnomAD4 genome AF: 0.0110 AC: 1681 AN: 152156 Hom.: 20 Cov.: 32 AF XY: 0.0120 AC XY: 891 AN XY: 74384

Gnomad4 AFR AF: 0.00267

Gnomad4 AMR AF: 0.00654

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00250

Gnomad4 FIN AF: 0.0359

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.0107 Hom.: 5

Bravo AF: 0.00857

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0111

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	ABCC2: BP4, BS1, BS2 -

Dubin-Johnson syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

ABCC2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	6.7
Dann	Benign	0.72

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: rs113646094; hg19: chr10-101564012; COSMIC: COSV64988276;