10-99804255-C-G

Variant names:

• chr10-99804255-C-G
• rs113646094
• NM_000392.5:c.1446C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000392.5(ABCC2):​c.1446C>G​(p.Thr482Thr) 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:6
• Conservation: PhyloP100: 0.293
• Publications: 17 publications found

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]

ABCC2 Gene-Disease associations (from GenCC):

• Dubin-Johnson syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 255993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000392.5. 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
	ABCC2	NM_000392.5	MANE Select	c.1446C>G	p.Thr482Thr	synonymous	Exon 10 of 32	NP_000383.2	Q92887

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC2	ENST00000647814.1	MANE Select	c.1446C>G	p.Thr482Thr	synonymous	Exon 10 of 32	ENSP00000497274.1	Q92887

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

GnomAD2 exomes AF: 0.0102 AC: 2567 AN: 251050 AF XY: 0.0102

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 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

African (AFR) AF: 0.00161 AC: 54 AN: 33480

American (AMR) AF: 0.00326 AC: 146 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0120 AC: 313 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00297 AC: 256 AN: 86248

European-Finnish (FIN) AF: 0.0280 AC: 1494 AN: 53418

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5760

European-Non Finnish (NFE) AF: 0.0125 AC: 13915 AN: 1111972

Other (OTH) AF: 0.00896 AC: 541 AN: 60390

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

African (AFR) AF: 0.00267 AC: 111 AN: 41514

American (AMR) AF: 0.00654 AC: 100 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00250 AC: 12 AN: 4808

European-Finnish (FIN) AF: 0.0359 AC: 380 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0148 AC: 1009 AN: 67994

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Dubin-Johnson syndrome (2)
-	-	1	ABCC2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.7
DANN	Benign	0.72
PhyloP100		0.29
Mutation Taster		=99/1	polymorphism

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: rs113646094; hg19: chr10-101564012;