chr22-25221635-A-G

Variant names:

• chr22-25221635-A-G
• rs739315
• NM_000496.3:c.54+152A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000496.3(CRYBB2):​c.54+152A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 645,064 control chromosomes in the GnomAD database, including 59,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11870 hom., cov: 33)
  • Exomes 𝑓: 0.44 (47627 hom.)
• Consequence: CRYBB2 NM_000496.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.79
• Publications: 8 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 22-25221635-A-G is Benign according to our data. Variant chr22-25221635-A-G is described in ClinVar as Benign. ClinVar VariationId is 1258808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB2	NM_000496.3	MANE Select	c.54+152A>G		intron	N/A	NP_000487.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB2	ENST00000398215.3	TSL:1 MANE Select	c.54+152A>G		intron	N/A	ENSP00000381273.2
	CRYBB2	ENST00000651629.1		c.54+152A>G		intron	N/A	ENSP00000498905.1

Frequencies

GnomAD3 genomes AF: 0.389 AC: 59013 AN: 151894 Hom.: 11862 Cov.: 33

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.421

GnomAD4 exome AF: 0.435 AC: 214661 AN: 493050 Hom.: 47627 AF XY: 0.437 AC XY: 114554 AN XY: 262240

African (AFR) AF: 0.273 AC: 3954 AN: 14480

American (AMR) AF: 0.447 AC: 13717 AN: 30710

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 7169 AN: 15784

East Asian (EAS) AF: 0.512 AC: 15595 AN: 30442

South Asian (SAS) AF: 0.447 AC: 23632 AN: 52926

European-Finnish (FIN) AF: 0.440 AC: 14299 AN: 32512

Middle Eastern (MID) AF: 0.448 AC: 1423 AN: 3178

European-Non Finnish (NFE) AF: 0.431 AC: 123112 AN: 285704

Other (OTH) AF: 0.431 AC: 11760 AN: 27314

GnomAD4 genome AF: 0.388 AC: 59055 AN: 152014 Hom.: 11870 Cov.: 33 AF XY: 0.392 AC XY: 29146 AN XY: 74294

African (AFR) AF: 0.277 AC: 11484 AN: 41464

American (AMR) AF: 0.400 AC: 6120 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1601 AN: 3466

East Asian (EAS) AF: 0.455 AC: 2350 AN: 5168

South Asian (SAS) AF: 0.450 AC: 2164 AN: 4804

European-Finnish (FIN) AF: 0.441 AC: 4658 AN: 10558

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.431 AC: 29268 AN: 67948

Other (OTH) AF: 0.425 AC: 897 AN: 2112

Alfa AF: 0.414 Hom.: 16853

Bravo AF: 0.380

Asia WGS AF: 0.473 AC: 1643 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.11
DANN	Benign	0.58
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs739315; hg19: chr22-25617602;