5-173233053-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004387.4(NKX2-5):c.491C>A(p.Ser164*) variant causes a stop gained 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 (★★).
Frequency
Consequence
NM_004387.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NKX2-5 | NM_004387.4 | c.491C>A | p.Ser164* | stop_gained | Exon 2 of 2 | ENST00000329198.5 | NP_004378.1 | |
NKX2-5 | NM_001166176.2 | c.*290C>A | 3_prime_UTR_variant | Exon 2 of 2 | NP_001159648.1 | |||
NKX2-5 | NM_001166175.2 | c.*444C>A | 3_prime_UTR_variant | Exon 2 of 2 | NP_001159647.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NKX2-5 | ENST00000329198.5 | c.491C>A | p.Ser164* | stop_gained | Exon 2 of 2 | 1 | NM_004387.4 | ENSP00000327758.4 | ||
NKX2-5 | ENST00000424406 | c.*444C>A | 3_prime_UTR_variant | Exon 2 of 2 | 1 | ENSP00000395378.2 | ||||
NKX2-5 | ENST00000521848 | c.*290C>A | 3_prime_UTR_variant | Exon 2 of 2 | 2 | ENSP00000427906.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1451904Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 721604
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Atrial septal defect 7 Pathogenic:1
This sequence change creates a premature translational stop signal (p.Ser164*) in the NKX2-5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 161 amino acid(s) of the NKX2-5 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with congenital heart disease (PMID: 32369864). ClinVar contains an entry for this variant (Variation ID: 519074). This variant disrupts a region of the NKX2-5 protein in which other variant(s) (p.Ala262Argfs*32) have been determined to be pathogenic (PMID: 22920929). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Cardiovascular phenotype Pathogenic:1
The p.S164* pathogenic mutation (also known as c.491C>A), located in coding exon 2 of the NKX2-5 gene, results from a C to A substitution at nucleotide position 491. This changes the amino acid from a serine to a stop codon within coding exon 2. This alteration is expected to result in loss of function by premature protein truncation. Truncating variants in the NKX2-5 gene are well-reported as disease-causing in individuals with septal defects and atrioventricular block (Schott JJ et al. Science, 1998 Jul;281:108-11; Benson DW et al. J. Clin. Invest., 1999 Dec;104:1567-73). As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at