rs4822752

Variant names:

• chr22-26615456-C-T
• rs4822752
• NM_001887.4:c.180+684G>A

Variant summary

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

The NM_001887.4(CRYBB1):​c.180+684G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 151,970 control chromosomes in the GnomAD database, including 25,560 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 0.58 (25560 hom., cov: 32)
• Consequence: CRYBB1 NM_001887.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0290
• Publications: 10 publications found

Genes affected

CRYBB1 (HGNC:2397): (crystallin beta B1) 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, undergoes extensive cleavage at its N-terminal extension during lens maturation. It is also a member of a gene cluster with beta-A4, beta-B2, and beta-B3. [provided by RefSeq, Jul 2008]

CRYBA4 (HGNC:2396): (crystallin beta A4) 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 acidic group member, is part of a gene cluster with beta-B1, beta-B2, and beta-B3. [provided by RefSeq, Jul 2008]

CRYBA4 Gene-Disease associations (from GenCC):

• cataract 23

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• cataract - microcornea syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset lamellar 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 = 0.777 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001887.4. 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
	CRYBB1	NM_001887.4	MANE Select	c.180+684G>A		intron	N/A	NP_001878.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB1	ENST00000647684.1	MANE Select	c.180+684G>A		intron	N/A	ENSP00000497249.1

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87344 AN: 151850 Hom.: 25519 Cov.: 32

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.661

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.617

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

GnomAD4 genome AF: 0.575 AC: 87442 AN: 151970 Hom.: 25560 Cov.: 32 AF XY: 0.582 AC XY: 43246 AN XY: 74248

African (AFR) AF: 0.567 AC: 23510 AN: 41430

American (AMR) AF: 0.662 AC: 10112 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 2194 AN: 3472

East Asian (EAS) AF: 0.797 AC: 4123 AN: 5174

South Asian (SAS) AF: 0.761 AC: 3671 AN: 4826

European-Finnish (FIN) AF: 0.583 AC: 6138 AN: 10534

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35836 AN: 67946

Other (OTH) AF: 0.620 AC: 1306 AN: 2106

Alfa AF: 0.552 Hom.: 61628

Bravo AF: 0.582

Asia WGS AF: 0.774 AC: 2692 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	0.25
DANN	Benign	0.72
PhyloP100		-0.029
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: rs4822752; hg19: chr22-27011420;