22-25225624-C-T

Variant names:

• chr22-25225624-C-T
• rs5752084
• NM_000496.3:c.173+588C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000398215.3(CRYBB2):​c.173+588C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 152,066 control chromosomes in the GnomAD database, including 18,834 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (18834 hom., cov: 32)
• Consequence: CRYBB2 ENST00000398215.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.853 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000398215.3. 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.173+588C>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.173+588C>T		intron	N/A	ENSP00000381273.2
	CRYBB2	ENST00000651629.1		c.173+588C>T		intron	N/A	ENSP00000498905.1

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73731 AN: 151948 Hom.: 18818 Cov.: 32

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.875

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.517

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.485 AC: 73775 AN: 152066 Hom.: 18834 Cov.: 32 AF XY: 0.492 AC XY: 36577 AN XY: 74326

African (AFR) AF: 0.356 AC: 14759 AN: 41478

American (AMR) AF: 0.541 AC: 8264 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2032 AN: 3472

East Asian (EAS) AF: 0.874 AC: 4522 AN: 5174

South Asian (SAS) AF: 0.669 AC: 3224 AN: 4820

European-Finnish (FIN) AF: 0.513 AC: 5416 AN: 10558

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.497 AC: 33791 AN: 67962

Other (OTH) AF: 0.524 AC: 1108 AN: 2114

Alfa AF: 0.508 Hom.: 14585

Bravo AF: 0.486

Asia WGS AF: 0.728 AC: 2530 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.0
DANN	Benign	0.41
PhyloP100		1.3
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: rs5752084; hg19: chr22-25621591;