17-59681366-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_004859.4(CLTC):c.3137G>A(p.Arg1046His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_004859.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLTC | NM_004859.4 | c.3137G>A | p.Arg1046His | missense_variant | Exon 20 of 32 | ENST00000269122.8 | NP_004850.1 | |
CLTC | NM_001288653.2 | c.3149G>A | p.Arg1050His | missense_variant | Exon 20 of 32 | NP_001275582.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250954Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135616
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461674Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727134
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Intellectual disability, autosomal dominant 56 Uncertain:1
The CLTC c.3149G>A (p.Arg1050His) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is located in a CHCR repeat of the heavy chain arm of the CLTC protein in which other de novo missense variants and small in-frame indels have been previously reported in individuals with CLTC-related neurodevelopmental disorder (Nabais Sa et al. 2020). The p.Arg1050His variant is reported at a frequency of 0.000033 in the South Asian population in version 2.1.1 of the Genome Aggregation Database, though this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. The variant is predicted to be deleterious by a majority of in silico predictors, but no functional studies have been conducted. Based on the available evidence, the p.Arg1050His variant is classified as a variant of uncertain significance for CLTC-related intellectual disability. -
Inborn genetic diseases Uncertain:1
The c.3137G>A (p.R1046H) alteration is located in coding exon 20 of the CLTC gene. This alteration results from a G to A substitution at nucleotide position 3137, causing the arginine (R) at amino acid position 1046 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/250954) total alleles studied. The highest observed frequency was 0.003% (1/30608) of South Asian alleles. This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at