rs36021462
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 4P and 13B. PM1PM5BP4_StrongBP6BS1BS2
The NM_001278116.2(L1CAM):c.2302G>A(p.Val768Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,209,763 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,359 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V768F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001278116.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
L1CAM | NM_001278116.2 | c.2302G>A | p.Val768Ile | missense_variant | Exon 19 of 29 | ENST00000370060.7 | NP_001265045.1 | |
L1CAM | NM_000425.5 | c.2302G>A | p.Val768Ile | missense_variant | Exon 18 of 28 | NP_000416.1 | ||
L1CAM | NM_024003.3 | c.2302G>A | p.Val768Ile | missense_variant | Exon 18 of 27 | NP_076493.1 | ||
L1CAM | NM_001143963.2 | c.2287G>A | p.Val763Ile | missense_variant | Exon 17 of 26 | NP_001137435.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00187 AC: 209AN: 111851Hom.: 0 Cov.: 22 AF XY: 0.00188 AC XY: 64AN XY: 34007
GnomAD3 exomes AF: 0.00214 AC: 392AN: 183219Hom.: 1 AF XY: 0.00276 AC XY: 187AN XY: 67707
GnomAD4 exome AF: 0.00331 AC: 3629AN: 1097862Hom.: 7 Cov.: 31 AF XY: 0.00357 AC XY: 1296AN XY: 363232
GnomAD4 genome AF: 0.00186 AC: 208AN: 111901Hom.: 0 Cov.: 22 AF XY: 0.00185 AC XY: 63AN XY: 34067
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:5
- -
- -
- -
- -
This variant is associated with the following publications: (PMID: 30487145, 22222883, 9268105) -
- -
not specified Benign:4
- -
- -
Variant summary: L1CAM c.2302G>A (p.Val768Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 204982 control chromosomes, predominantly at a frequency of 0.0063 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in L1CAM causing L1 Syndrome (0.0021 vs 0.0065), allowing no conclusion about variant significance. Although reported in the literature, to our knowledge, no occurrence/penetrant association of c.2302G>A in individuals affected with L1 Syndrome and no supporting experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
- -
Spastic paraplegia Benign:1
- -
Inborn genetic diseases Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Hereditary spastic paraplegia Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at