rs4455261

Positions:

• chr22-25207051-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004076.5(CRYBB3):​c.475G>A​(p.Val159Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,613,160 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (33 hom.)
• Consequence: CRYBB3 NM_004076.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.29

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 -18 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.00620237).
• BP6: Variant 22-25207051-G-A is Benign according to our data. Variant chr22-25207051-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 466359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-25207051-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00806 (1227/152308) while in subpopulation AFR AF= 0.0274 (1140/41580). AF 95% confidence interval is 0.0261. There are 17 homozygotes in gnomad4. There are 570 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBB3	NM_004076.5	c.475G>A	p.Val159Ile	missense_variant	6/6	ENST00000215855.7	NP_004067.1
CRYBB3	XM_047441147.1	c.475G>A	p.Val159Ile	missense_variant	5/5		XP_047297103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB3	ENST00000215855.7	c.475G>A	p.Val159Ile	missense_variant	6/6	1	NM_004076.5	ENSP00000215855	P1
CRYBB3	ENST00000404334.1	c.332G>A	p.Gly111Asp	missense_variant	5/5	3		ENSP00000386123

Frequencies

GnomAD3 genomes AF: 0.00802 AC: 1220 AN: 152190 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

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: 0.000206

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00267 AC: 667 AN: 249442 Hom.: 10 AF XY: 0.00184 AC XY: 249 AN XY: 135092

Gnomad AFR exome AF: 0.0277

Gnomad AMR exome AF: 0.00494

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000152

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00102 AC: 1496 AN: 1460852 Hom.: 33 Cov.: 31 AF XY: 0.000806 AC XY: 586 AN XY: 726824

Gnomad4 AFR exome AF: 0.0309

Gnomad4 AMR exome AF: 0.00490

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000702

Gnomad4 OTH exome AF: 0.00255

GnomAD4 genome AF: 0.00806 AC: 1227 AN: 152308 Hom.: 17 Cov.: 32 AF XY: 0.00765 AC XY: 570 AN XY: 74478

Gnomad4 AFR AF: 0.0274

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00160 Hom.: 5

Bravo AF: 0.00933

ESP6500AA AF: 0.0245 AC: 108

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00319 AC: 387

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 22 multiple types Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 12, 2022	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0062	T
MetaSVM	Uncertain	-0.27	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	0.35	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.021	D
Sift4G	Benign	0.076	T
Vest4		0.68
MVP		0.76
ClinPred		0.033	T
GERP RS		4.9

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: rs4455261; hg19: chr22-25603018;