rs397517184
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP2BS1_Supporting
The NM_020297.4(ABCC9):āc.1603T>Cā(p.Tyr535His) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,612,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.000028 ( 0 hom. )
Consequence
ABCC9
NM_020297.4 missense
NM_020297.4 missense
Scores
1
8
9
Clinical Significance
Conservation
PhyloP100: 3.84
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 Uncertain_significance. Variant got 2 ACMG points.
PM1
?
In a domain ABC transmembrane type-1 1 (size 300) in uniprot entity ABCC9_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_020297.4
PP2
?
Missense variant where missense usually causes diseases, ABCC9
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000281 (41/1460848) while in subpopulation MID AF= 0.00156 (9/5760). AF 95% confidence interval is 0.000815. There are 0 homozygotes in gnomad4_exome. There are 26 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC9 | NM_020297.4 | c.1603T>C | p.Tyr535His | missense_variant | 12/40 | ENST00000261200.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC9 | ENST00000261200.9 | c.1603T>C | p.Tyr535His | missense_variant | 12/40 | 5 | NM_020297.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250994Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135638
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GnomAD4 exome AF: 0.0000281 AC: 41AN: 1460848Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26AN XY: 726744
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 31, 2012 | Variant classified as Uncertain Significance - Favor Benign. The Tyr535His varia nt in ABCC9 has not been reported in the literature nor previously identified by our laboratory. Tyrosine (Tyr) at position 535 is not well conserved in evoluti on (chicken and fish both carry the variant amino acid (His) at this position), suggesting that this change may be tolerated. Other computational analyses (bioc hemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) also suggest that this variant may not impact the protein, though this information is not predict ive enough to rule out pathogenicity. This variant is more likely benign but add itional data is needed to establish this with confidence. - |
Likely benign, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Sep 28, 2016 | - - |
Dilated cardiomyopathy 1O Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 45389). This missense change has been observed in individual(s) with left ventricular noncompaction (PMID: 33500567). This variant is present in population databases (rs397517184, gnomAD 0.006%). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 535 of the ABCC9 protein (p.Tyr535His). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2021 | Has not been previously published as pathogenic or benign to our knowledge Reported in ClinVar (ClinVar Variant ID# 45389; Landrum et al., 2016) Observed in 7/250994 (0.0028%) alleles in large population cohorts (Lek et al., 2016) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 31, 2023 | The p.Y535H variant (also known as c.1603T>C), located in coding exon 10 of the ABCC9 gene, results from a T to C substitution at nucleotide position 1603. The tyrosine at codon 535 is replaced by histidine, an amino acid with similar properties. This alteration was reported in an exome sequencing cohort, a cohort of subjects with suspected with genetic disorders and a left ventricular non-compaction (LVNC) cohort (Mazzarotto F et al. Genet Med, 2021 May;23:856-864; Monies D et al. Am J Hum Genet, 2019 Jun;104:1182-1201; Saudi Mendeliome Group. Genome Biol, 2015 Jun;16:134). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Hypertrichotic osteochondrodysplasia Cantu type;C1837839:Dilated cardiomyopathy 1O;C3279695:Atrial fibrillation, familial, 12;C5676904:Intellectual disability and myopathy syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 20, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.;M
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;.;B
Vest4
MutPred
Gain of disorder (P = 0.0267);.;Gain of disorder (P = 0.0267);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at