12-21842440-C-T

Position:

• chr12-21842440-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_020297.4(ABCC9):​c.3347G>A​(p.Arg1116His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1116C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC9 NM_020297.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.87

Genes affected

ABCC9 (HGNC:60): (ATP binding cassette subfamily C member 9) 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 thought to form ATP-sensitive potassium channels in cardiac, skeletal, and vascular and non-vascular smooth muscle. Protein structure suggests a role as the drug-binding channel-modulating subunit of the extra-pancreatic ATP-sensitive potassium channels. Mutations in this gene are associated with cardiomyopathy dilated type 1O. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2011]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 71) in uniprot entity ABCC9_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_020297.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-21842441-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, ABCC9
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864
• PP5: Variant 12-21842440-C-T is Pathogenic according to our data. Variant chr12-21842440-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 35533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21842440-C-T is described in Lovd as [Pathogenic]. Variant chr12-21842440-C-T is described in Lovd as [Likely_pathogenic]. Variant chr12-21842440-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC9	NM_020297.4	c.3347G>A	p.Arg1116His	missense_variant	29/40	ENST00000261200.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC9	ENST00000261200.9	c.3347G>A	p.Arg1116His	missense_variant	29/40	5	NM_020297.4	P4
	ENST00000539874.1	n.331+11246C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrichotic osteochondrodysplasia Cantu type Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously described as disease-causing in the literature and has been identified once in our laboratory as a de novo mutation in a 7-year-old male with macrosomia, decreased white matter on MRI, pulmonary hypertension, cardiomegaly, hydronephrosis, advanced bone age, vocal cord paralysis, coarse features, and increased joint motility. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 18, 2012	- -
Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -

Dilated cardiomyopathy 1O Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2023

ClinVar contains an entry for this variant (Variation ID: 35533). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1116 amino acid residue in ABCC9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22610116, 27316244; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ABCC9 function (PMID: 22610116). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC9 protein function. This missense change has been observed in individual(s) with clinical features of Cantu syndrome (PMID: 22610116, 23307537, 25590979, 27316244). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs387907227, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1116 of the ABCC9 protein (p.Arg1116His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.1	M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.031	D;T;D
Sift4G	Uncertain	0.029	D;T;D
Polyphen		1.0	D;.;P
Vest4		0.67
MutPred		0.70		Gain of disorder (P = 0.0824);.;Gain of disorder (P = 0.0824);
MVP		0.95
MPC		1.8
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.68
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs387907227; hg19: chr12-21995374;