22-25225156-C-A

Position:

• chr22-25225156-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000496.3(CRYBB2):​c.173+120C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 755,972 control chromosomes in the GnomAD database, including 18,886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3774 hom., cov: 32)
  • Exomes 𝑓: 0.21 (15112 hom.)
• Consequence: CRYBB2 NM_000496.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.309

Genes affected

CRYBB2 (HGNC:2398): (crystallin beta B2) 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-B3. A chain-terminating mutation was found to cause type 2 cerulean cataracts. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 22-25225156-C-A is Benign according to our data. Variant chr22-25225156-C-A is described in ClinVar as [Benign]. Clinvar id is 1280176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-25225156-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBB2	NM_000496.3	c.173+120C>A		intron_variant		ENST00000398215.3	NP_000487.1
CRYBB2	XM_006724141.4	c.173+120C>A		intron_variant			XP_006724204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB2	ENST00000398215.3	c.173+120C>A		intron_variant		1	NM_000496.3	ENSP00000381273	P1
CRYBB2	ENST00000651629.1	c.173+120C>A		intron_variant				ENSP00000498905	P1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32812 AN: 151964 Hom.: 3777 Cov.: 32

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.0335

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.206

GnomAD4 exome AF: 0.212 AC: 128207 AN: 603890 Hom.: 15112 AF XY: 0.213 AC XY: 69802 AN XY: 327688

Gnomad4 AFR exome AF: 0.214

Gnomad4 AMR exome AF: 0.127

Gnomad4 ASJ exome AF: 0.195

Gnomad4 EAS exome AF: 0.0279

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.166

Gnomad4 NFE exome AF: 0.253

Gnomad4 OTH exome AF: 0.218

GnomAD4 genome AF: 0.216 AC: 32816 AN: 152082 Hom.: 3774 Cov.: 32 AF XY: 0.208 AC XY: 15487 AN XY: 74344

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.0336

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.202

Alfa AF: 0.238 Hom.: 2220

Bravo AF: 0.217

Asia WGS AF: 0.103 AC: 359 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.5
DANN	Benign	0.47

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: rs9306412; hg19: chr22-25621123;