22-26601766-A-T

Position:

• chr22-26601766-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001887.4(CRYBB1):​c.575+113T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,544,878 control chromosomes in the GnomAD database, including 36,791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (3118 hom., cov: 31)
  • Exomes 𝑓: 0.21 (33673 hom.)
• Consequence: CRYBB1 NM_001887.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.885

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 22-26601766-A-T is Benign according to our data. Variant chr22-26601766-A-T is described in ClinVar as [Benign]. Clinvar id is 1273779.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBB1	NM_001887.4	c.575+113T>A		intron_variant		ENST00000647684.1	NP_001878.1
CRYBA4	XM_006724140.4	c.-239+4683A>T		intron_variant			XP_006724203.1
CRYBB1	XM_011529899.4	c.575+113T>A		intron_variant			XP_011528201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB1	ENST00000647684.1	c.575+113T>A		intron_variant			NM_001887.4	ENSP00000497249	P1
	ENST00000668614.1	n.56+4683A>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26698 AN: 151422 Hom.: 3097 Cov.: 31

Gnomad AFR AF: 0.0552

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.375

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.214

GnomAD4 exome AF: 0.208 AC: 289793 AN: 1393338 Hom.: 33673 AF XY: 0.212 AC XY: 146893 AN XY: 692664

Gnomad4 AFR exome AF: 0.0475

Gnomad4 AMR exome AF: 0.413

Gnomad4 ASJ exome AF: 0.197

Gnomad4 EAS exome AF: 0.343

Gnomad4 SAS exome AF: 0.369

Gnomad4 FIN exome AF: 0.219

Gnomad4 NFE exome AF: 0.188

Gnomad4 OTH exome AF: 0.211

GnomAD4 genome AF: 0.176 AC: 26736 AN: 151540 Hom.: 3118 Cov.: 31 AF XY: 0.183 AC XY: 13591 AN XY: 74066

Gnomad4 AFR AF: 0.0551

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.192

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.375

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.221

Alfa AF: 0.172 Hom.: 312

Bravo AF: 0.178

Asia WGS AF: 0.427 AC: 1482 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.81
DANN	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2301441; hg19: chr22-26997730;