rs147344332

Positions:

• chr22-25231737-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PP3_Moderate PP5 BS2_Supporting

The NM_000496.3(CRYBB2):​c.583T>G​(p.Trp195Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000905 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: CRYBB2 NM_000496.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.55

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Beta-crystallin B2 (size 203) in uniprot entity CRBB2_HUMAN there are 23 pathogenic changes around while only 1 benign (96%) in NM_000496.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843
• PP5: Variant 22-25231737-T-G is Pathogenic according to our data. Variant chr22-25231737-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217350.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBB2	NM_000496.3	c.583T>G	p.Trp195Gly	missense_variant	6/6	ENST00000398215.3	NP_000487.1
CRYBB2	XM_006724141.4	c.583T>G	p.Trp195Gly	missense_variant	6/6		XP_006724204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB2	ENST00000398215.3	c.583T>G	p.Trp195Gly	missense_variant	6/6	1	NM_000496.3	ENSP00000381273.2
CRYBB2	ENST00000651629.1	c.583T>G	p.Trp195Gly	missense_variant	6/6			ENSP00000498905.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152130 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000111 AC: 28 AN: 251356 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135872

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000930 AC: 136 AN: 1461870 Hom.: 0 Cov.: 33 AF XY: 0.0000949 AC XY: 69 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000953

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152130 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74314

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000104 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental cataract Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Eye Genetics Research Group, Children's Medical Research Institute

Jan 09, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.75
MVP		0.59
MPC		1.6
ClinPred		0.83	D
GERP RS		4.0
Varity_R		0.97

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

Other links and lift over

dbSNP: rs147344332; hg19: chr22-25627704; COSMIC: COSV101236780;