chr22-25207123-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1BS2

The NM_004076.5(CRYBB3):​c.547G>T​(p.Glu183Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000658 in 1,613,658 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 3 hom., cov: 32)
Exomes 𝑓: 0.00060 ( 4 hom. )

Consequence

CRYBB3
NM_004076.5 stop_gained

Scores

5
1
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 7.34
Variant links:
Genes affected
CRYBB3 (HGNC:2400): (crystallin beta B3) Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Beta-crystallins, the most heterogeneous, differ by the presence of the C-terminal extension (present in the basic group, none in the acidic group). Beta-crystallins form aggregates of different sizes and are able to self-associate to form dimers or to form heterodimers with other beta-crystallins. This gene, a beta basic group member, is part of a gene cluster with beta-A4, beta-B1, and beta-B2. Mutations in this gene result in cataract congenital nuclear autosomal recessive type 2. [provided by RefSeq, Feb 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00125 (191/152320) while in subpopulation AFR AF= 0.00257 (107/41576). AF 95% confidence interval is 0.00218. There are 3 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CRYBB3NM_004076.5 linkuse as main transcriptc.547G>T p.Glu183Ter stop_gained 6/6 ENST00000215855.7 NP_004067.1
CRYBB3XM_047441147.1 linkuse as main transcriptc.547G>T p.Glu183Ter stop_gained 5/5 XP_047297103.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CRYBB3ENST00000215855.7 linkuse as main transcriptc.547G>T p.Glu183Ter stop_gained 6/61 NM_004076.5 ENSP00000215855 P1
CRYBB3ENST00000404334.1 linkuse as main transcriptc.*62G>T 3_prime_UTR_variant 5/53 ENSP00000386123

Frequencies

GnomAD3 genomes
AF:
0.00125
AC:
191
AN:
152202
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00258
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.0179
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.00117
AC:
292
AN:
249886
Hom.:
2
AF XY:
0.00112
AC XY:
151
AN XY:
135420
show subpopulations
Gnomad AFR exome
AF:
0.00282
Gnomad AMR exome
AF:
0.000289
Gnomad ASJ exome
AF:
0.0190
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000311
Gnomad OTH exome
AF:
0.00180
GnomAD4 exome
AF:
0.000596
AC:
871
AN:
1461338
Hom.:
4
Cov.:
31
AF XY:
0.000600
AC XY:
436
AN XY:
726998
show subpopulations
Gnomad4 AFR exome
AF:
0.00326
Gnomad4 AMR exome
AF:
0.000358
Gnomad4 ASJ exome
AF:
0.0183
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000143
Gnomad4 OTH exome
AF:
0.00181
GnomAD4 genome
AF:
0.00125
AC:
191
AN:
152320
Hom.:
3
Cov.:
32
AF XY:
0.00119
AC XY:
89
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.00257
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.0179
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.00121
Hom.:
4
Bravo
AF:
0.00165
ESP6500AA
AF:
0.00295
AC:
13
ESP6500EA
AF:
0.000814
AC:
7
ExAC
AF:
0.000923
AC:
112
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000382
EpiControl
AF:
0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cataract 22 multiple types Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 15, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
CRYBB3-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 21, 2023The CRYBB3 c.547G>T variant is predicted to result in premature protein termination (p.Glu183*). This variant occurs within the terminal exon of CRYBB3 and is predicted to shorten the coding sequence by 28 amino acids. This variant was reported in a family with congenital cataracts; however, all affected family members harbored a pathogenic variant in EPHA2. The CRYBB3 (p.Glu183*) did not segregate with the disorder and was excluded from further analysis (Reis et al. 2014. PubMed ID: 24940039). This variant was also reported in the heterozygous state in an individual with early-onset high myopia (eoHM); however, this patient also had additional variants in other candidate genes and all variants were reported to be maternally-inherited (Patient OFT-00332 in González-Iglesias et al 2022. PubMed ID: 35457050). This variant is reported in 1.9% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including two homozygous individuals (http://gnomad.broadinstitute.org/variant/22-25603090-G-T). Loss of function has not been a well documented cause of CRYBB3-related disease (Human Gene Mutation Database). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2023CRYBB3: BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
43
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.98
D
MutationTaster
Benign
1.0
D;D
Vest4
0.58
GERP RS
4.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs147328317; hg19: chr22-25603090; API