rs137852820
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2
The NM_001367721.1(CASK):c.1186C>T(p.Pro396Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,202,665 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts 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. P396A) has been classified as Uncertain significance.
Frequency
Consequence
NM_001367721.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASK | NM_001367721.1 | c.1186C>T | p.Pro396Ser | missense_variant | 13/27 | ENST00000378163.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASK | ENST00000378163.7 | c.1186C>T | p.Pro396Ser | missense_variant | 13/27 | 5 | NM_001367721.1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000223 AC: 25AN: 112279Hom.: 0 Cov.: 23 AF XY: 0.000261 AC XY: 9AN XY: 34455
GnomAD3 exomes AF: 0.0000602 AC: 11AN: 182614Hom.: 0 AF XY: 0.0000447 AC XY: 3AN XY: 67134
GnomAD4 exome AF: 0.0000413 AC: 45AN: 1090386Hom.: 0 Cov.: 26 AF XY: 0.0000421 AC XY: 15AN XY: 356230
GnomAD4 genome ? AF: 0.000223 AC: 25AN: 112279Hom.: 0 Cov.: 23 AF XY: 0.000261 AC XY: 9AN XY: 34455
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | CASK: BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 14, 2020 | This variant is associated with the following publications: (PMID: 19377476, 23871722, 33090494, 24505460, 21954287, 22452838, 19847910, 21735175, 29426960, 25886057, 20029458) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 07, 2018 | - - |
FG syndrome 4 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2009 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2018 | This alteration is classified as likely 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. - |
Syndromic X-linked intellectual disability Najm type Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 06, 2020 | This variant, that leads to the substitution of proline in codon 396 for serine, has been previously reported in medical literature to segregate with the phenotype of X-linked intellectual deficiency in one family (PMID: 19377476). However, functional studies demonstrate that it results in a structurally stable protein and interactions with liprin-α, Mint-1 and Veli are preserved (PMID: 24505460). In addition, it is observed at a higher than expected frequency in population databases, including 5 hemizygous individuals (gnomAD v2.1.1). Therefore, this variant was considered to be likely benign. - |
Intellectual disability, CASK-related, X-linked Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at