chr5-173232902-A-AGGC
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP3BP6
The NM_004387.4(NKX2-5):c.641_642insGCC(p.Pro213dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.0000523 in 1,606,388 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P214P) has been classified as Likely benign.
Frequency
Consequence
NM_004387.4 inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NKX2-5 | NM_004387.4 | c.641_642insGCC | p.Pro213dup | inframe_insertion | 2/2 | ENST00000329198.5 | |
NKX2-5 | NM_001166175.2 | c.*594_*595insGCC | 3_prime_UTR_variant | 2/2 | |||
NKX2-5 | NM_001166176.2 | c.*440_*441insGCC | 3_prime_UTR_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NKX2-5 | ENST00000329198.5 | c.641_642insGCC | p.Pro213dup | inframe_insertion | 2/2 | 1 | NM_004387.4 | P1 | |
NKX2-5 | ENST00000424406.2 | c.*594_*595insGCC | 3_prime_UTR_variant | 2/2 | 1 | ||||
NKX2-5 | ENST00000521848.1 | c.*440_*441insGCC | 3_prime_UTR_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152070Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000155 AC: 34AN: 218836Hom.: 0 AF XY: 0.000116 AC XY: 14AN XY: 120622
GnomAD4 exome AF: 0.0000523 AC: 76AN: 1454318Hom.: 0 Cov.: 34 AF XY: 0.0000498 AC XY: 36AN XY: 723164
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152070Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74278
ClinVar
Submissions by phenotype
Atrial septal defect 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2023 | This variant, c.639_641dup, results in the insertion of 1 amino acid(s) of the NKX2-5 protein (p.Pro214dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs777382725, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with NKX2-5-related conditions (PMID: 34374102). This variant is also known as p.P213dup. ClinVar contains an entry for this variant (Variation ID: 410968). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Sep 28, 2017 | Found in a 14 yo female with incomplete RBBB on EKG and a history of two syncopal episodes during exercise. Her echocardiogram and cardiac MRI were read as normal. p.Pro214dup (c.639_641dupGCC) in the NKX2.5 gene (NM_004387.3) Chromosome location 5:172659912 -- / GGC Based on the information reviewed below, we classify this as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. It may be a benign ethnicity-specific variant that is more common in individuals with Latino ancestry like our patient. The NKX2.5 gene is associated with atrial septal defect with or without atrioventricular conduction defects (MedGen UID: 400040), among other things. Our patient has not shown signs of this phenotype. This variant has not previously been reported in the literature in association with disease, according to the Invitae report. It is present, however, in population databases at an allele count that is higher than expected for a pathogenic variant. This is an in-frame insertion of a Proline amino acid amid a string of 7 Prolines. This variant was reported in at least 36 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 23 out of 15,976 Latinos (for the highest allele frequency: 0.07%), 6 South Asians, 4 non-Finnish Europeans, 2 Africans, and 1 “Other†ancestry individual. 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. The curators made an effort to exclude individuals with severe pediatric diseases. - |
Tetralogy of Fallot Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 29, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at