12-21864490-C-T
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
Consequence
NM_020297.4 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000552 AC: 84AN: 152060Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000148 AC: 37AN: 250480Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 135454
GnomAD4 exome AF: 0.0000473 AC: 67AN: 1415502Hom.: 0 Cov.: 26 AF XY: 0.0000354 AC XY: 25AN XY: 706882
GnomAD4 genome AF: 0.000552 AC: 84AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.000565 AC XY: 42AN XY: 74398
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
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. -
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not provided Uncertain:1Benign:1
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. -
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Dilated cardiomyopathy 1O Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at