3-42688951-C-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2
The NM_152393.4(KLHL40):c.1504C>A(p.Leu502Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,080 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. L502F) has been classified as Uncertain significance.
Frequency
Consequence
NM_152393.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLHL40 | NM_152393.4 | c.1504C>A | p.Leu502Ile | missense_variant | 4/6 | ENST00000287777.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLHL40 | ENST00000287777.5 | c.1504C>A | p.Leu502Ile | missense_variant | 4/6 | 1 | NM_152393.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251460Hom.: 1 AF XY: 0.0000809 AC XY: 11AN XY: 135906
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461852Hom.: 2 Cov.: 32 AF XY: 0.0000371 AC XY: 27AN XY: 727228
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74370
ClinVar
Submissions by phenotype
Nemaline myopathy 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 28, 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 578731). This variant has not been reported in the literature in individuals affected with KLHL40-related conditions. This variant is present in population databases (rs766195312, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 502 of the KLHL40 protein (p.Leu502Ile). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at