rs147831812

chr22-25201434-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004076.5(CRYBB3):c.38C>G(p.Ala13Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00576 in 1,613,456 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (39 hom.)
• Consequence: CRYBB3 NM_004076.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 5.05

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007799864).
• BP6: Variant 22-25201434-C-G is Benign according to our data. Variant chr22-25201434-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 340949.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00389 (593/152262) while in subpopulation NFE AF= 0.00657 (447/68024). AF 95% confidence interval is 0.00607. There are 3 homozygotes in gnomad4. There are 266 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBB3	NM_004076.5	c.38C>G	p.Ala13Gly	missense_variant	2/6	ENST00000215855.7
CRYBB3	XM_047441147.1	c.38C>G	p.Ala13Gly	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBB3	ENST00000215855.7	c.38C>G	p.Ala13Gly	missense_variant	2/6	1	NM_004076.5	P1
CRYBB3	ENST00000404334.1	c.38C>G	p.Ala13Gly	missense_variant	2/5	3

Frequencies

GnomAD3 genomes AF: 0.00390 AC: 594 AN: 152144 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00657

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00452 AC: 1137 AN: 251342 Hom.: 11 AF XY: 0.00465 AC XY: 632 AN XY: 135884

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00624

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00656

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00595 AC: 8701 AN: 1461194 Hom.: 39 Cov.: 34 AF XY: 0.00593 AC XY: 4311 AN XY: 726880

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.00213

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00677

Gnomad4 FIN exome AF: 0.00296

Gnomad4 NFE exome AF: 0.00675

Gnomad4 OTH exome AF: 0.00474

GnomAD4 genome AF: 0.00389 AC: 593 AN: 152262 Hom.: 3 Cov.: 32 AF XY: 0.00357 AC XY: 266 AN XY: 74444

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.00657

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00583 Hom.: 3

Bravo AF: 0.00363

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00468 AC: 568

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00594

EpiControl AF: 0.00539

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

The c.38C>G (p.A13G) alteration is located in exon 2 (coding exon 1) of the CRYBB3 gene. This alteration results from a C to G substitution at nucleotide position 38, causing the alanine (A) at amino acid position 13 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital nuclear cataract Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

CRYBB3: BP4, BS2 -

Cataract 22 multiple types Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.037	T;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.44	B;.
Vest4		0.33
MVP		0.81
MPC		0.22
ClinPred		0.028	T
GERP RS		4.8
Varity_R		0.21
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs147831812; hg19: chr22-25597401;