chr12-21842440-C-T
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_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
Consequence
NM_020297.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
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
ClinVar
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at