22-25221379-C-T

Variant names:

• chr22-25221379-C-T
• rs16979774
• NM_000496.3:c.-26-25C>T

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.-26-25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,502,510 control chromosomes in the GnomAD database, including 963 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.018 (93 hom., cov: 32)
  • Exomes 𝑓: 0.020 (870 hom.)
• Consequence: CRYBB2 NM_000496.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.211
• Publications: 7 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: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 22-25221379-C-T is Benign according to our data. Variant chr22-25221379-C-T is described in ClinVar as Benign. ClinVar VariationId is 1294002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.135 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.-26-25C>T		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.-26-25C>T		intron	N/A	ENSP00000381273.2
	CRYBB2	ENST00000651629.1		c.-26-25C>T		intron	N/A	ENSP00000498905.1

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2723 AN: 152160 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.00495

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0378

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0712

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0350 AC: 8789 AN: 251100 AF XY: 0.0338

Gnomad AFR exome AF: 0.00382

Gnomad AMR exome AF: 0.0802

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.150

Gnomad FIN exome AF: 0.00439

Gnomad NFE exome AF: 0.00968

Gnomad OTH exome AF: 0.0232

GnomAD4 exome AF: 0.0198 AC: 26748 AN: 1350230 Hom.: 870 Cov.: 20 AF XY: 0.0205 AC XY: 13928 AN XY: 678094

African (AFR) AF: 0.00280 AC: 87 AN: 31126

American (AMR) AF: 0.0756 AC: 3367 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00428 AC: 109 AN: 25462

East Asian (EAS) AF: 0.143 AC: 5587 AN: 39092

South Asian (SAS) AF: 0.0589 AC: 4946 AN: 83968

European-Finnish (FIN) AF: 0.00482 AC: 257 AN: 53326

Middle Eastern (MID) AF: 0.00595 AC: 33 AN: 5546

European-Non Finnish (NFE) AF: 0.0109 AC: 11064 AN: 1010418

Other (OTH) AF: 0.0229 AC: 1298 AN: 56740

GnomAD4 genome AF: 0.0179 AC: 2720 AN: 152280 Hom.: 93 Cov.: 32 AF XY: 0.0190 AC XY: 1414 AN XY: 74458

African (AFR) AF: 0.00493 AC: 205 AN: 41560

American (AMR) AF: 0.0379 AC: 580 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.144 AC: 743 AN: 5162

South Asian (SAS) AF: 0.0715 AC: 345 AN: 4828

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0105 AC: 714 AN: 68020

Other (OTH) AF: 0.0189 AC: 40 AN: 2116

Alfa AF: 0.0162 Hom.: 72

Bravo AF: 0.0206

Asia WGS AF: 0.0890 AC: 308 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

Nov 11, 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	-0.81
CADD	Benign	8.0
DANN	Benign	0.63
PhyloP100		0.21
BranchPoint Hunter		4.0
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: rs16979774; hg19: chr22-25617346; COSMIC: COSV68005256;