rs149787233
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_001289808.2(CRYAB):c.116C>T(p.Pro39Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000189 in 1,612,866 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P39A) has been classified as Uncertain significance.
Frequency
Consequence
NM_001289808.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRYAB | NM_001289808.2 | c.116C>T | p.Pro39Leu | missense_variant | 1/3 | ENST00000650687.2 | |
CRYAB | NM_001289807.1 | c.116C>T | p.Pro39Leu | missense_variant | 2/4 | ||
CRYAB | NM_001368245.1 | c.116C>T | p.Pro39Leu | missense_variant | 2/4 | ||
CRYAB | NM_001885.3 | c.116C>T | p.Pro39Leu | missense_variant | 2/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRYAB | ENST00000650687.2 | c.116C>T | p.Pro39Leu | missense_variant | 1/3 | NM_001289808.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000184 AC: 28AN: 152078Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000242 AC: 60AN: 248140Hom.: 0 AF XY: 0.000216 AC XY: 29AN XY: 134030
GnomAD4 exome AF: 0.000190 AC: 277AN: 1460788Hom.: 0 Cov.: 31 AF XY: 0.000204 AC XY: 148AN XY: 726544
GnomAD4 genome ? AF: 0.000184 AC: 28AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74272
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 23, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2023 | Previously reported in an individual with left ventricular non-compaction who also harbored variants in the LMNA and MYLK2 genes (Miszalski-Jamka et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28798025, 32420686) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 21, 2023 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 12, 2013 | The Pro39Leu variant in CRYAB has not been reported in individuals with cardiomy opathy, but has been identified in 5/8594 European American chromosomes by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1497872 33). Computational analyses (biochemical amino acid properties, conservation, Al ignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an im pact to the protein. Additional information is needed to fully assess the clinic al significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 01, 2016 | - - |
Dilated cardiomyopathy 1II Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 39 of the CRYAB protein (p.Pro39Leu). This variant is present in population databases (rs149787233, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with CRYAB-related conditions. ClinVar contains an entry for this variant (Variation ID: 178013). 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: "Probably Damaging"; 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 30, 2023 | - - |
Fatal infantile hypertonic myofibrillar myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Myofibrillar myopathy 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 27, 2023 | 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. - |
Cataract 16 multiple types Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at