rs2027889

Variant names:

• chr22-25201659-C-T
• rs2027889
• NM_004076.5:c.75+188C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004076.5(CRYBB3):​c.75+188C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.072 in 152,230 control chromosomes in the GnomAD database, including 1,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.072 (1266 hom., cov: 32)
• Consequence: CRYBB3 NM_004076.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00600
• Publications: 0 publications found

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]

CRYBB3 Gene-Disease associations (from GenCC):

• cataract 22 multiple types

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• early-onset anterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset non-syndromic cataract

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 22-25201659-C-T is Benign according to our data. Variant chr22-25201659-C-T is described in ClinVar as Benign. ClinVar VariationId is 1273709.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004076.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB3	NM_004076.5	MANE Select	c.75+188C>T		intron	N/A	NP_004067.1	P26998

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB3	ENST00000215855.7	TSL:1 MANE Select	c.75+188C>T		intron	N/A	ENSP00000215855.2	P26998
	CRYBB3	ENST00000404334.1	TSL:3	c.75+188C>T		intron	N/A	ENSP00000386123.1	B1AHR5

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10943 AN: 152112 Hom.: 1267 Cov.: 32

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.0506

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

GnomAD4 genome AF: 0.0720 AC: 10967 AN: 152230 Hom.: 1266 Cov.: 32 AF XY: 0.0683 AC XY: 5082 AN XY: 74448

African (AFR) AF: 0.247 AC: 10246 AN: 41478

American (AMR) AF: 0.0346 AC: 530 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00104 AC: 71 AN: 68028

Other (OTH) AF: 0.0501 AC: 106 AN: 2116

Alfa AF: 0.0537 Hom.: 88

Bravo AF: 0.0838

Asia WGS AF: 0.0160 AC: 57 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.7
DANN	Benign	0.57
PhyloP100		-0.0060
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2027889; hg19: chr22-25597626;