rs3729754
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_ModerateBP6BS1
The NM_004387.4(NKX2-5):c.632C>T(p.Pro211Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000358 in 1,603,988 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_004387.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NKX2-5 | NM_004387.4 | c.632C>T | p.Pro211Leu | missense_variant | Exon 2 of 2 | ENST00000329198.5 | NP_004378.1 | |
NKX2-5 | NM_001166176.2 | c.*431C>T | 3_prime_UTR_variant | Exon 2 of 2 | NP_001159648.1 | |||
NKX2-5 | NM_001166175.2 | c.*585C>T | 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.632C>T | p.Pro211Leu | missense_variant | Exon 2 of 2 | 1 | NM_004387.4 | ENSP00000327758.4 | ||
NKX2-5 | ENST00000424406 | c.*585C>T | 3_prime_UTR_variant | Exon 2 of 2 | 1 | ENSP00000395378.2 | ||||
NKX2-5 | ENST00000521848 | c.*431C>T | 3_prime_UTR_variant | Exon 2 of 2 | 2 | ENSP00000427906.1 |
Frequencies
GnomAD3 genomes AF: 0.000269 AC: 41AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000248 AC: 55AN: 221568Hom.: 0 AF XY: 0.000245 AC XY: 30AN XY: 122328
GnomAD4 exome AF: 0.000367 AC: 533AN: 1451642Hom.: 0 Cov.: 35 AF XY: 0.000363 AC XY: 262AN XY: 721682
GnomAD4 genome AF: 0.000269 AC: 41AN: 152346Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74492
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
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Reported in two related individuals with atrial septal defects and pacemakers, however, it was absent in two other affected family members (PMID: 12112663); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26334177, 31824610, 34070861, 35272499, 12112663, 31430255) -
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NKX2-5-related disorder Uncertain:1
The NKX2-5 c.632C>T variant is predicted to result in the amino acid substitution p.Pro211Leu. This variant has been reported in two family members with atrial septal defects however, this variant did not segregate with disease in two additional affected family members (Gutierrez-Roelens et al. 2002. PubMed ID: 12112663). This has also been reported with uncertain significance in two individuals with congenital hypothyroidism and in a healthy newborn; both individuals with congenital hypothyroidism had additional variants reported (Table 1, Santos-Silva et al. 2019. PubMed ID: 31430255; Table 1, Larrivée-Vanier et al. 2022. PubMed ID: 35272499; Table S4, Bodian et al. 2016. PubMed ID: 26334177). This variant is reported in 0.045% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Atrial septal defect 7 Benign:1
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Cardiovascular phenotype Benign:1
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