chr11-111911560-C-T
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_001289808.2(CRYAB):c.165G>A(p.Leu55=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,612,794 control chromosomes in the GnomAD database, including 349 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.013 ( 23 hom., cov: 32)
Exomes 𝑓: 0.019 ( 326 hom. )
Consequence
CRYAB
NM_001289808.2 synonymous
NM_001289808.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.166
Genes affected
CRYAB (HGNC:2389): (crystallin alpha B) Mammalian lens crystallins are divided into alpha, beta, and gamma families. Alpha crystallins are composed of two gene products: alpha-A and alpha-B, for acidic and basic, respectively. Alpha crystallins can be induced by heat shock and are members of the small heat shock protein (HSP20) family. They act as molecular chaperones although they do not renature proteins and release them in the fashion of a true chaperone; instead they hold them in large soluble aggregates. These heterogeneous aggregates consist of 30-40 subunits; the alpha-A and alpha-B subunits have a 3:1 ratio, respectively. Two additional functions of alpha crystallins are an autokinase activity and participation in the intracellular architecture. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Alpha-A and alpha-B gene products are differentially expressed; alpha-A is preferentially restricted to the lens and alpha-B is expressed widely in many tissues and organs. Elevated expression of alpha-B crystallin occurs in many neurological diseases; a missense mutation cosegregated in a family with a desmin-related myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2019]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
?
Variant 11-111911560-C-T is Benign according to our data. Variant chr11-111911560-C-T is described in ClinVar as [Benign]. Clinvar id is 44233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-111911560-C-T is described in Lovd as [Benign]. Variant chr11-111911560-C-T is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=0.166 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0132 (2014/152176) while in subpopulation SAS AF= 0.0239 (115/4812). AF 95% confidence interval is 0.0204. There are 23 homozygotes in gnomad4. There are 904 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd at 2015 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRYAB | NM_001289808.2 | c.165G>A | p.Leu55= | synonymous_variant | 1/3 | ENST00000650687.2 | |
CRYAB | NM_001289807.1 | c.165G>A | p.Leu55= | synonymous_variant | 2/4 | ||
CRYAB | NM_001368245.1 | c.165G>A | p.Leu55= | synonymous_variant | 2/4 | ||
CRYAB | NM_001885.3 | c.165G>A | p.Leu55= | synonymous_variant | 2/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRYAB | ENST00000650687.2 | c.165G>A | p.Leu55= | synonymous_variant | 1/3 | NM_001289808.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0133 AC: 2015AN: 152058Hom.: 23 Cov.: 32
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GnomAD3 exomes AF: 0.0154 AC: 3821AN: 248196Hom.: 55 AF XY: 0.0166 AC XY: 2222AN XY: 134142
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GnomAD4 exome AF: 0.0191 AC: 27861AN: 1460618Hom.: 326 Cov.: 31 AF XY: 0.0191 AC XY: 13867AN XY: 726454
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ClinVar
Significance: Benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:7
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 02, 2011 | Leu55Leu in exon 1 of CRYAB: This variant is not expected to have clinical signi ficance because it does not alter an amino acid, is not located within the splic e consensus sequence, and has been identified in 1.5% (166/10758) of chromosomes from a broad, though clinically and ethnically unspecified population (dbSNP rs 2228387). Leu55Leu in exon 1 of CRYAB (rs2228387; allele frequency = 1.5%, 166/ 10758) - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 25, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 07, 2018 | - - |
Dilated cardiomyopathy 1II Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Myofibrillar Myopathy, Dominant Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Fatal infantile hypertonic myofibrillar myopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 15, 2015 | 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. - |
Cataract 16 multiple types Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at