rs387907228

Positions:

• chr12-21842441-G-A

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.3346C>T​(p.Arg1116Cys) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1116H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC9 NM_020297.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.64

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 chr12-21842440-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.
• PP2: Missense variant where missense usually causes diseases, ABCC9
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871
• PP5: Variant 12-21842441-G-A is Pathogenic according to our data. 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. Variant chr12-21842441-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC9	NM_020297.4	c.3346C>T	p.Arg1116Cys	missense_variant	29/40	ENST00000261200.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC9	ENST00000261200.9	c.3346C>T	p.Arg1116Cys	missense_variant	29/40	5	NM_020297.4	P4
	ENST00000539874.1	n.331+11247G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrichotic osteochondrodysplasia Cantu type Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 18, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	-	- -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Dilated cardiomyopathy 1O Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2019

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 observed in individuals with ABCC9-related conditions (PMID: 25590979, 23307537, 22610116), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in individuals with Cantu syndrome and observed to segregate with clinical features of Cantu syndrome in a family, and observed de novo in an individual with clinical features of Cantu syndrome (PMID: 22610116, 27316244, Invitae). ClinVar contains an entry for this variant (Variation ID: 35534). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 1116 of the ABCC9 protein (p.Arg1116Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. -

Kleefstra syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Jun 11, 2018

[ACMG/AMP: PM2, PM5, PP2, PP3, PP5] This alteration is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2019

The p.R1116C variant (also known as c.3346C>T), located in coding exon 27 of the ABCC9 gene, results from a C to T substitution at nucleotide position 3346. The arginine at codon 1116 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals reported to have Cantú syndrome, and was reported to segregate with Cantú syndrome-associated features in one family (Harakalova M et al. Nat. Genet., 2012 May;44:793-6; Leon Guerrero CR et al. Neurology, 2016 07;87:270-6). A different variant affecting this codon (p.R1116H, c.3347G>A) has also been reported in association with Cantú syndrome, including de novo occurrence (Harakalova M et al. Nat. Genet., 2012 May;44:793-6; Czeschik JC et al. Am. J. Med. Genet. A, 2013 Feb;161A:295-300; Zhu X et al. Genet. Med., 2015 Oct;17:774-81). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.9	M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.014	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.91
MutPred		0.70		Loss of disorder (P = 0.0362);.;Loss of disorder (P = 0.0362);
MVP		0.96
MPC		1.9
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.65
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs387907228; hg19: chr12-21995375; COSMIC: COSV53983185;