rs72558201

Variant names:

• chr10-99836193-A-G
• rs72558201
• NM_000392.5:c.3517A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-99836193-A-G
• chr10-99836193-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000392.5(ABCC2):​c.3517A>G​(p.Ile1173Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1173F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ABCC2 NM_000392.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.29
• Publications: 14 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: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000295976 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-99836193-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 8418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC2	NM_000392.5	c.3517A>G	p.Ile1173Val	missense_variant	Exon 25 of 32	ENST00000647814.1	NP_000383.2
ABCC2	XM_006717630.4	c.2821A>G	p.Ile941Val	missense_variant	Exon 20 of 27		XP_006717693.1
ABCC2	XM_047424598.1	c.3517A>G	p.Ile1173Val	missense_variant	Exon 25 of 26		XP_047280554.1
ABCC2	XR_945604.4	n.3722A>G		non_coding_transcript_exon_variant	Exon 25 of 30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC2	ENST00000647814.1	c.3517A>G	p.Ile1173Val	missense_variant	Exon 25 of 32		NM_000392.5	ENSP00000497274.1
ENSG00000295976	ENST00000734671.1	n.51-2014T>C		intron_variant	Intron 1 of 1
ENSG00000295976	ENST00000734672.1	n.523-2014T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251492 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.0	M;M
PhyloP100		7.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.93	.;N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	D;D
Vest4		0.63
MutPred		0.71		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.79
MPC		0.26
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.57
gMVP		0.43
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72558201; hg19: chr10-101595950;