rs387907228
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_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
NM_020297.4 missense
Scores
10
7
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;D
Vest4
MutPred
Loss of disorder (P = 0.0362);.;Loss of disorder (P = 0.0362);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at