14-74494103-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_194279.4(ISCA2):c.125G>A(p.Ser42Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000184 in 1,573,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S42I) has been classified as Uncertain significance.
Frequency
Consequence
NM_194279.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ISCA2 | NM_194279.4 | c.125G>A | p.Ser42Asn | missense_variant | 2/4 | ENST00000556816.6 | |
ISCA2 | NM_001272007.2 | c.125G>A | p.Ser42Asn | missense_variant | 2/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ISCA2 | ENST00000556816.6 | c.125G>A | p.Ser42Asn | missense_variant | 2/4 | 1 | NM_194279.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000268 AC: 5AN: 186580Hom.: 0 AF XY: 0.0000295 AC XY: 3AN XY: 101754
GnomAD4 exome AF: 0.0000197 AC: 28AN: 1421262Hom.: 0 Cov.: 31 AF XY: 0.0000156 AC XY: 11AN XY: 704262
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 25, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with ISCA2-related conditions. This variant is present in population databases (rs749217402, gnomAD 0.007%). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 42 of the ISCA2 protein (p.Ser42Asn). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at