dbSNP rs9608378: CRYBB3:p.His113Asn (chr22-25205229-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_004076.5(CRYBB3):c.337C>A(p.His113Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 151,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H113D) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Consequence

CRYBB3
NM_004076.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.24

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]

CRYBB3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a chain Beta-crystallin B3 (size 210) in uniprot entity CRBB3_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_004076.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2059347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBB3	NM_004076.5 link	c.337C>A	p.His113Asn	missense_variant	Exon 5 of 6	ENST00000215855.7	NP_004067.1	P26998
CRYBB3	XM_047441147.1 link	c.337C>A	p.His113Asn	missense_variant	Exon 4 of 5		XP_047297103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBB3	ENST00000215855.7 link	c.337C>A	p.His113Asn	missense_variant	Exon 5 of 6	1	NM_004076.5	ENSP00000215855.2		P26998
CRYBB3	ENST00000404334.1 link	c.327+1334C>A		intron_variant	Intron 4 of 4	3		ENSP00000386123.1		B1AHR5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151912

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74162

show subpopulations

Gnomad4 AFR

AF:

0.0000726

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.0050

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.28

M_CAP

Benign

0.047

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.29

PrimateAI

Benign

0.39

PROVEAN

Benign

1.5

REVEL

Benign

0.21

Sift

Benign

0.077

Sift4G

Benign

0.27

Polyphen

0.0

Vest4

0.12

MutPred

0.23

Gain of sheet (P = 0.0477);

MVP

0.63

MPC

0.16

ClinPred

0.80

GERP RS

5.3

Varity_R

0.14

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over