rs199652160
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4
The NM_007098.4(CLTCL1):c.988G>A(p.Glu330Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000633 in 1,613,948 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_007098.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLTCL1 | ENST00000427926.6 | c.988G>A | p.Glu330Lys | missense_variant | Exon 7 of 33 | 1 | NM_007098.4 | ENSP00000441158.1 | ||
CLTCL1 | ENST00000621271.4 | c.988G>A | p.Glu330Lys | missense_variant | Exon 7 of 32 | 1 | ENSP00000485020.1 | |||
CLTCL1 | ENST00000615606.4 | n.1008G>A | non_coding_transcript_exon_variant | Exon 7 of 30 | 1 | |||||
CLTCL1 | ENST00000617103.4 | n.988G>A | non_coding_transcript_exon_variant | Exon 7 of 31 | 1 | ENSP00000480709.1 |
Frequencies
GnomAD3 genomes AF: 0.000506 AC: 77AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000490 AC: 122AN: 249198Hom.: 0 AF XY: 0.000414 AC XY: 56AN XY: 135192
GnomAD4 exome AF: 0.000646 AC: 944AN: 1461620Hom.: 1 Cov.: 31 AF XY: 0.000648 AC XY: 471AN XY: 727094
GnomAD4 genome AF: 0.000505 AC: 77AN: 152328Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30AN XY: 74484
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
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The E330K variant in the CLTCL1 gene has been reported previously, in the homozygous state, in three siblingswith significant intellectual disability, global developmental delay, absent pain sensation, self mutilating behavior,ophthalmological abnormalities, hypotonia, bone abnormalities, dysmorphic features, and brain abnormalities onMRI, with childhood death in two of the three siblings (Nahorski et al., 2015). The variant has also been reported inthe presence of another CLTCL1 variant in one individual with autism (Chahrour et al., 2012). The E330K variantwas not observed with any significant frequency in approximately 6200 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations. The E330K variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at aposition that is conserved across species and in silico analysis predicts this variant is probably damaging to theprotein structure/function. Therefore, we interpret E330K as a likely pathogenic variant, however, the possibility itmay be a rare benign variant cannot be excluded. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at