rs2071859

Variant names:

• chr22-26608336-G-T
• rs2071859
• NM_001887.4:c.300-315C>A

Variant summary

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

The NM_001887.4(CRYBB1):​c.300-315C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 152,174 control chromosomes in the GnomAD database, including 1,754 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (1754 hom., cov: 33)
• Consequence: CRYBB1 NM_001887.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.352
• Publications: 5 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]

ENSG00000286326 (HGNC:):

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-26608336-G-T is Benign according to our data. Variant chr22-26608336-G-T is described in ClinVar as Benign. ClinVar VariationId is 1250226.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBB1	NM_001887.4	c.300-315C>A		intron_variant	Intron 3 of 5	ENST00000647684.1	NP_001878.1
CRYBB1	XM_011529899.4	c.300-315C>A		intron_variant	Intron 3 of 5		XP_011528201.1
CRYBA4	XM_006724140.4	c.3+274G>T		intron_variant	Intron 3 of 7		XP_006724203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBB1	ENST00000647684.1	c.300-315C>A		intron_variant	Intron 3 of 5		NM_001887.4	ENSP00000497249.1
ENSG00000286326	ENST00000668614.2	n.493+274G>T		intron_variant	Intron 2 of 2
ENSG00000286326	ENST00000840228.1	n.426+274G>T		intron_variant	Intron 2 of 2
CRYBB1	ENST00000647569.1	n.-7C>A		upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21739 AN: 152056 Hom.: 1751 Cov.: 33

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.138

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

GnomAD4 genome AF: 0.143 AC: 21744 AN: 152174 Hom.: 1754 Cov.: 33 AF XY: 0.144 AC XY: 10710 AN XY: 74376

African (AFR) AF: 0.130 AC: 5387 AN: 41496

American (AMR) AF: 0.166 AC: 2539 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 637 AN: 3472

East Asian (EAS) AF: 0.303 AC: 1570 AN: 5174

South Asian (SAS) AF: 0.241 AC: 1163 AN: 4818

European-Finnish (FIN) AF: 0.101 AC: 1066 AN: 10598

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.131 AC: 8877 AN: 68010

Other (OTH) AF: 0.137 AC: 289 AN: 2114

Alfa AF: 0.138 Hom.: 243

Bravo AF: 0.145

Asia WGS AF: 0.214 AC: 741 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.63
DANN	Benign	0.59
PhyloP100		-0.35
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: rs2071859; hg19: chr22-27004300;