NM_004387.4:c.73C>T
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_004387.4(NKX2-5):c.73C>T(p.Arg25Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,612,236 control chromosomes in the GnomAD database, including 53 homozygotes. 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 Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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NKX2-5 | NM_004387.4 | c.73C>T | p.Arg25Cys | missense_variant | Exon 1 of 2 | ENST00000329198.5 | NP_004378.1 | |
NKX2-5 | NM_001166176.2 | c.73C>T | p.Arg25Cys | missense_variant | Exon 1 of 2 | NP_001159648.1 | ||
NKX2-5 | NM_001166175.2 | c.73C>T | p.Arg25Cys | missense_variant | Exon 1 of 2 | NP_001159647.1 | ||
NKX2-5 | XM_017009071.3 | c.73C>T | p.Arg25Cys | missense_variant | Exon 1 of 2 | XP_016864560.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NKX2-5 | ENST00000329198.5 | c.73C>T | p.Arg25Cys | missense_variant | Exon 1 of 2 | 1 | NM_004387.4 | ENSP00000327758.4 | ||
NKX2-5 | ENST00000424406.2 | c.73C>T | p.Arg25Cys | missense_variant | Exon 1 of 2 | 1 | ENSP00000395378.2 | |||
NKX2-5 | ENST00000521848.1 | c.73C>T | p.Arg25Cys | missense_variant | Exon 1 of 2 | 2 | ENSP00000427906.1 | |||
NKX2-5 | ENST00000517440.1 | c.73C>T | p.Arg25Cys | missense_variant | Exon 1 of 2 | 4 | ENSP00000429905.1 |
Frequencies
GnomAD3 genomes AF: 0.00991 AC: 1509AN: 152208Hom.: 23 Cov.: 33
GnomAD3 exomes AF: 0.00343 AC: 832AN: 242556Hom.: 12 AF XY: 0.00296 AC XY: 393AN XY: 132950
GnomAD4 exome AF: 0.00201 AC: 2929AN: 1459910Hom.: 30 Cov.: 31 AF XY: 0.00193 AC XY: 1401AN XY: 726278
GnomAD4 genome AF: 0.00992 AC: 1511AN: 152326Hom.: 23 Cov.: 33 AF XY: 0.00891 AC XY: 664AN XY: 74488
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:3
Arg25Cys in exon 1 of NKX2-5: This variant has been reported in a large number o f individuals with congenital heart disease (Akcaboy 2008, Benson 1999, DeLuca 2 010, Esposito 2009, Goli-Pereira 2010, Goldmuntz 2001, McElhinny 2003, Raunch 20 10, Stallmeyer 2010). This variant is now considered to be benign based on its h igh population frequency (2.6%) in the Black population (97/3694 chromosomes, NH LBI Exome Variant Project http://evs.gs.washington.edu/EVS/). -
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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Atrial septal defect 7 Benign:2
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Persistent truncus arteriosus Pathogenic:1
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Hypoplastic left heart syndrome 2 Pathogenic:1
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Aortic arch interruption Pathogenic:1
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Hypothyroidism, congenital, nongoitrous, 5 Pathogenic:1
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Tetralogy of Fallot Pathogenic:1
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not provided Benign:1
NKX2-5: BS1, BS2 -
Congenital heart disease Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as 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