10-99844450-C-T

Variant names:

• chr10-99844450-C-T
• rs3740066
• NM_000392.5:c.3972C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000392.5(ABCC2):​c.3972C>T​(p.Ile1324Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 1,613,504 control chromosomes in the GnomAD database, including 105,110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8466 hom., cov: 33)
  • Exomes 𝑓: 0.36 (96644 hom.)
• Consequence: ABCC2 NM_000392.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0690

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 10-99844450-C-T is Benign according to our data. Variant chr10-99844450-C-T is described in ClinVar as [Benign]. Clinvar id is 196101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-99844450-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.069 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC2	NM_000392.5	c.3972C>T	p.Ile1324Ile	synonymous_variant	Exon 28 of 32	ENST00000647814.1	NP_000383.2
ABCC2	XM_006717630.4	c.3276C>T	p.Ile1092Ile	synonymous_variant	Exon 23 of 27		XP_006717693.1
ABCC2	XR_945604.4	n.4177C>T		non_coding_transcript_exon_variant	Exon 28 of 30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC2	ENST00000647814.1	c.3972C>T	p.Ile1324Ile	synonymous_variant	Exon 28 of 32		NM_000392.5	ENSP00000497274.1
ABCC2	ENST00000649459.1	n.320C>T		non_coding_transcript_exon_variant	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49678 AN: 152002 Hom.: 8473 Cov.: 33

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.346

GnomAD2 exomes AF: 0.341 AC: 85500 AN: 250980 AF XY: 0.343

Gnomad AFR exome AF: 0.257

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.345

Gnomad EAS exome AF: 0.232

Gnomad FIN exome AF: 0.341

Gnomad NFE exome AF: 0.371

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.361 AC: 528097 AN: 1461384 Hom.: 96644 Cov.: 51 AF XY: 0.361 AC XY: 262439 AN XY: 727046

Gnomad4 AFR exome AF: 0.255 AC: 8541 AN: 33474

Gnomad4 AMR exome AF: 0.348 AC: 15551 AN: 44722

Gnomad4 ASJ exome AF: 0.347 AC: 9069 AN: 26132

Gnomad4 EAS exome AF: 0.228 AC: 9068 AN: 39700

Gnomad4 SAS exome AF: 0.328 AC: 28262 AN: 86256

Gnomad4 FIN exome AF: 0.342 AC: 18170 AN: 53060

Gnomad4 NFE exome AF: 0.374 AC: 416299 AN: 1111888

Gnomad4 Remaining exome AF: 0.352 AC: 21255 AN: 60386

GnomAD4 genome AF: 0.327 AC: 49695 AN: 152120 Hom.: 8466 Cov.: 33 AF XY: 0.326 AC XY: 24231 AN XY: 74362

Gnomad4 AFR AF: 0.260 AC: 0.259876 AN: 0.259876

Gnomad4 AMR AF: 0.344 AC: 0.343562 AN: 0.343562

Gnomad4 ASJ AF: 0.351 AC: 0.351297 AN: 0.351297

Gnomad4 EAS AF: 0.229 AC: 0.229312 AN: 0.229312

Gnomad4 SAS AF: 0.322 AC: 0.322273 AN: 0.322273

Gnomad4 FIN AF: 0.335 AC: 0.334783 AN: 0.334783

Gnomad4 NFE AF: 0.366 AC: 0.365823 AN: 0.365823

Gnomad4 OTH AF: 0.346 AC: 0.345825 AN: 0.345825

Alfa AF: 0.338 Hom.: 7765

Bravo AF: 0.323

Asia WGS AF: 0.272 AC: 947 AN: 3478

EpiCase AF: 0.367

EpiControl AF: 0.372

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17997497, 24743544, 21541183, 25087612) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dubin-Johnson syndrome Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

Dec 12, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCC2-related disorder Benign:1

Mar 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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	9.2
DANN	Benign	0.67
Mutation Taster		=99/1	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

Publications

LitVar

Other links and lift over

dbSNP: rs3740066; hg19: chr10-101604207; COSMIC: COSV64984370;