NM_000496.3:c.433C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1PP2

The NM_000496.3(CRYBB2):c.433C>T(p.Arg145Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R145Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CRYBB2
NM_000496.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.137

Publications

12 publications found

Variant links:

Genes affected

CRYBB2 (HGNC:2398): (crystallin beta B2) 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-B3. A chain-terminating mutation was found to cause type 2 cerulean cataracts. [provided by RefSeq, Jul 2008]

CRYBB2 Gene-Disease associations (from GenCC):

cataract 3 multiple types
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
cataract - microcornea syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cerulean cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset posterior subcapsular cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset sutural cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pulverulent cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
total early-onset cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CRYBB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000496.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.0723 (below the threshold of 3.09). Trascript score misZ: 1.7369 (below the threshold of 3.09). GenCC associations: The gene is linked to cataract 3 multiple types, pulverulent cataract, cataract - microcornea syndrome, early-onset posterior subcapsular cataract, total early-onset cataract, early-onset nuclear cataract, cerulean cataract, early-onset sutural cataract.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000496.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB2	NM_000496.3	MANE Select	c.433C>T	p.Arg145Trp	missense	Exon 5 of 6	NP_000487.1	P43320

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRYBB2	ENST00000398215.3	TSL:1 MANE Select	c.433C>T	p.Arg145Trp	missense	Exon 5 of 6	ENSP00000381273.2	P43320
CRYBB2	ENST00000651629.1		c.433C>T	p.Arg145Trp	missense	Exon 5 of 6	ENSP00000498905.1	P43320
CRYBB2	ENST00000855619.1		c.433C>T	p.Arg145Trp	missense	Exon 4 of 5	ENSP00000525678.1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251396

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727228

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1112000

Other (OTH)

AF:

0.0000331

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000129320), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.373

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74388

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000723

AC:

AN:

41474

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00251027), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.385

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000501

Hom.:

ExAC

AF:

0.0000494

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

CRYBB2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.073

MetaRNN

Uncertain

0.70

MetaSVM

Uncertain

0.56

MutationAssessor

Pathogenic

3.2

PhyloP100

0.14

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.6

REVEL

Pathogenic

0.75

Sift

Uncertain

0.011

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.64

MutPred

0.56

Loss of disorder (P = 0.0262)

MVP

0.75

MPC

1.3

ClinPred

0.98

GERP RS

1.2

Varity_R

0.70

Mutation Taster

=17/83

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over