rs554594996
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_017882.3(CLN6):c.749G>A(p.Arg250His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,614,082 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R250C) has been classified as Uncertain significance.
Frequency
Consequence
NM_017882.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLN6 | NM_017882.3 | c.749G>A | p.Arg250His | missense_variant | 7/7 | ENST00000249806.11 | |
CLN6 | NM_001411068.1 | c.845G>A | p.Arg282His | missense_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN6 | ENST00000249806.11 | c.749G>A | p.Arg250His | missense_variant | 7/7 | 1 | NM_017882.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152216Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000111 AC: 28AN: 251188Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135812
GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461748Hom.: 0 Cov.: 38 AF XY: 0.0000385 AC XY: 28AN XY: 727174
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152334Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74494
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 22, 2015 | p.Arg250His (CGC>CAC): c.749 G>A in exon 7 of the CLN6 gene (NM_017882.2). The Arg250His missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Arg250His in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is conservative, as Arginine and Histidine are both positively charged amino acids. It alters a position between the sixth and seventh transmembrane domains that is conserved through mammals but is not conserved in more distant species. Several in silico algorithms predict it may be damaging to protein structure/function, although another model suggests it may be benign. Therefore, based on the currently available information, it is unclear whether Arg250His is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). - |
Neuronal ceroid lipofuscinosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 27, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 250 of the CLN6 protein (p.Arg250His). This variant is present in population databases (rs554594996, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CLN6-related conditions. ClinVar contains an entry for this variant (Variation ID: 205175). 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: "Benign"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at