12-21864490-C-T
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1
The NM_020297.4(ABCC9):c.2199-13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000963 in 1,567,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 0 hom. )
Consequence
ABCC9
NM_020297.4 intron
NM_020297.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.849
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 Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.23).
BP6
Variant 12-21864490-C-T is Benign according to our data. Variant chr12-21864490-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228423.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000552 (84/152178) while in subpopulation AFR AF= 0.00195 (81/41528). AF 95% confidence interval is 0.00161. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000552 AC: 84AN: 152060Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000148 AC: 37AN: 250480Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 135454
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GnomAD4 exome AF: 0.0000473 AC: 67AN: 1415502Hom.: 0 Cov.: 26 AF XY: 0.0000354 AC XY: 25AN XY: 706882
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GnomAD4 genome 0.000552 AC: 84AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.000565 AC XY: 42AN XY: 74398
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
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 | Aug 10, 2017 | Variant classified as Uncertain Significance - Favor Benign. The c.2199-13G>A va riant in ABCC9 has been identified in our laboratory in one individual with dila ted cardiomyopathy. It has also been identified in 0.2% (22/10238) of African ch romosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitu te.org; dbSNP rs201226082). This variant has been reported in ClinVar (Variation ID: 228423). Computational tools do not suggest an impact on splicing, though t his information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the c.2199-13G>A variant is uncertain, its fr equency suggests that it is more likely to be benign. - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 06, 2024 | - - |
not provided Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 05, 2020 | - - |
| Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Sep 05, 2017 | c.2199-13G>A in intron 16 of the ABCC9 gene (NM_005691.2; 12:22017424C>T) The Laboratory for Molecular Medicine classifies this variant as a variant of uncertain significance. However, they state it is more likely to be benign. Given the absence of case data and its high prevalence in the general population, we consider this variant a variant of uncertain significance, likely benign, and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 2 unrelated (unpublished) cases of dilated cardiomyopathy (including this patient's family). The ABCC9 gene is most commonly associated with familial atrial fibrillation, dilated cardiomyopathy and hypertrichotic osteochondrodysplasia (Cantu syndrome). There is no published case data. This variant is present in ClinVar: GeneDx classifies this variant as likely benign. Per the test report, "computational tools do not suggest an impact on splicing, though this information is not predictive enough to rule out pathogenicity." The cytosine in the gDNA at position 2199 is moderately conserved across species. Neighboring nucleic acids are more strongly conserved. There are two other nearby intronic variants close to this one that are both classified as (likely) benign: c.2199-6T>C and c.2199-11T>C. The variant was reported online in 53 of 138,163 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 49 of 11,984 individuals of African descent (MAF=0.2%) and 4 of 17,148 individuals of Latino descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. - |
Dilated cardiomyopathy 1O Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2025 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at