3-42688701-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_152393.4(KLHL40):c.1405G>T(p.Gly469Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_152393.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461484Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727064
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74310
ClinVar
Submissions by phenotype
Nemaline myopathy 8 Pathogenic:2
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: 60513). This variant has been observed in individual(s) with nemaline myopathy (PMID: 23746549, 25721947). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with cysteine at codon 469 of the KLHL40 protein (p.Gly469Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at