rs3740066

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr10-99844450-C-T
• chr10-99844450-C-G

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 (★★). Synonymous variant affecting the same amino acid position (i.e. I1324I) has been classified as Uncertain significance.

• 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:8
• Conservation: PhyloP100: 0.0690
• Publications: 284 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

ENSG00000295976 (HGNC:):

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 VariationId is 196101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.3972C>T	p.Ile1324Ile	synonymous	Exon 28 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.3972C>T	p.Ile1324Ile	synonymous	Exon 28 of 32	ENSP00000497274.1	Q92887
	ABCC2	ENST00000649459.1		n.320C>T		non_coding_transcript_exon	Exon 2 of 5
	ENSG00000295976	ENST00000734671.1		n.50+211G>A		intron	N/A

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

African (AFR) AF: 0.255 AC: 8541 AN: 33474

American (AMR) AF: 0.348 AC: 15551 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 9069 AN: 26132

East Asian (EAS) AF: 0.228 AC: 9068 AN: 39700

South Asian (SAS) AF: 0.328 AC: 28262 AN: 86256

European-Finnish (FIN) AF: 0.342 AC: 18170 AN: 53060

Middle Eastern (MID) AF: 0.326 AC: 1882 AN: 5766

European-Non Finnish (NFE) AF: 0.374 AC: 416299 AN: 1111888

Other (OTH) 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

African (AFR) AF: 0.260 AC: 10789 AN: 41516

American (AMR) AF: 0.344 AC: 5251 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1219 AN: 3470

East Asian (EAS) AF: 0.229 AC: 1186 AN: 5172

South Asian (SAS) AF: 0.322 AC: 1554 AN: 4822

European-Finnish (FIN) AF: 0.335 AC: 3540 AN: 10574

Middle Eastern (MID) AF: 0.329 AC: 96 AN: 292

European-Non Finnish (NFE) AF: 0.366 AC: 24865 AN: 67970

Other (OTH) AF: 0.346 AC: 729 AN: 2108

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.2
DANN	Benign	0.67
PhyloP100		0.069
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

Other links and lift over

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