22-26609194-C-T

Variant names:

• chr22-26609194-C-T
• rs4822749
• NM_001887.4:c.300-1173G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001887.4(CRYBB1):​c.300-1173G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 152,190 control chromosomes in the GnomAD database, including 3,164 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 0.18 (3164 hom., cov: 32)
• Consequence: CRYBB1 NM_001887.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.480

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]

ENSG00000286326 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBB1	NM_001887.4	c.300-1173G>A		intron_variant	Intron 3 of 5	ENST00000647684.1	NP_001878.1
CRYBB1	XM_011529899.4	c.300-1173G>A		intron_variant	Intron 3 of 5		XP_011528201.1
CRYBA4	XM_006724140.4	c.3+1132C>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.300-1173G>A		intron_variant	Intron 3 of 5		NM_001887.4	ENSP00000497249.1
ENSG00000286326	ENST00000668614.1	n.297+1132C>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27015 AN: 152072 Hom.: 3143 Cov.: 32

Gnomad AFR AF: 0.0578

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.376

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.217

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

GnomAD4 genome AF: 0.178 AC: 27056 AN: 152190 Hom.: 3164 Cov.: 32 AF XY: 0.185 AC XY: 13749 AN XY: 74402

Gnomad4 AFR AF: 0.0577

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.194

Gnomad4 EAS AF: 0.376

Gnomad4 SAS AF: 0.377

Gnomad4 FIN AF: 0.220

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.224

Alfa AF: 0.179 Hom.: 321

Bravo AF: 0.179

Asia WGS AF: 0.430 AC: 1494 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.90
DANN	Benign	0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs4822749; hg19: chr22-27005158;