NM_000496.3:c.449+9G>A

Variant names:

• chr22-25229587-G-A
• rs4049505
• NM_000496.3:c.449+9G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000496.3(CRYBB2):​c.449+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,613,564 control chromosomes in the GnomAD database, including 388,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39477 hom., cov: 35)
  • Exomes 𝑓: 0.69 (349049 hom.)
• Consequence: CRYBB2 NM_000496.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.60
• Publications: 6 publications found

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]

CRYBB2 Gene-Disease associations (from GenCC):

• cataract 3 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• cataract - microcornea syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cerulean cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior subcapsular cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset sutural cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulverulent cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 22-25229587-G-A is Benign according to our data. Variant chr22-25229587-G-A is described in ClinVar as Benign. ClinVar VariationId is 256282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000496.3. 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
	CRYBB2	NM_000496.3	MANE Select	c.449+9G>A		intron	N/A	NP_000487.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB2	ENST00000398215.3	TSL:1 MANE Select	c.449+9G>A		intron	N/A	ENSP00000381273.2
	CRYBB2	ENST00000651629.1		c.449+9G>A		intron	N/A	ENSP00000498905.1

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108986 AN: 152134 Hom.: 39456 Cov.: 35

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.699

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.958

Gnomad SAS AF: 0.803

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.764

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.726

GnomAD2 exomes AF: 0.726 AC: 181914 AN: 250512 AF XY: 0.724

Gnomad AFR exome AF: 0.787

Gnomad AMR exome AF: 0.777

Gnomad ASJ exome AF: 0.682

Gnomad EAS exome AF: 0.956

Gnomad FIN exome AF: 0.653

Gnomad NFE exome AF: 0.668

Gnomad OTH exome AF: 0.694

GnomAD4 exome AF: 0.688 AC: 1005378 AN: 1461312 Hom.: 349049 Cov.: 69 AF XY: 0.691 AC XY: 502014 AN XY: 726946

African (AFR) AF: 0.787 AC: 26335 AN: 33472

American (AMR) AF: 0.769 AC: 34347 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 17737 AN: 26128

East Asian (EAS) AF: 0.961 AC: 38154 AN: 39696

South Asian (SAS) AF: 0.783 AC: 67537 AN: 86214

European-Finnish (FIN) AF: 0.649 AC: 34673 AN: 53386

Middle Eastern (MID) AF: 0.761 AC: 4390 AN: 5768

European-Non Finnish (NFE) AF: 0.665 AC: 739724 AN: 1111606

Other (OTH) AF: 0.704 AC: 42481 AN: 60372

GnomAD4 genome AF: 0.716 AC: 109059 AN: 152252 Hom.: 39477 Cov.: 35 AF XY: 0.716 AC XY: 53306 AN XY: 74450

African (AFR) AF: 0.783 AC: 32513 AN: 41548

American (AMR) AF: 0.699 AC: 10702 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 2329 AN: 3468

East Asian (EAS) AF: 0.958 AC: 4964 AN: 5182

South Asian (SAS) AF: 0.802 AC: 3875 AN: 4830

European-Finnish (FIN) AF: 0.645 AC: 6838 AN: 10608

Middle Eastern (MID) AF: 0.757 AC: 221 AN: 292

European-Non Finnish (NFE) AF: 0.668 AC: 45439 AN: 67996

Other (OTH) AF: 0.728 AC: 1540 AN: 2114

Alfa AF: 0.708 Hom.: 19831

Bravo AF: 0.728

Asia WGS AF: 0.859 AC: 2988 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cataract 3 multiple types (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.12
DANN	Benign	0.63
PhyloP100		-1.6
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: rs4049505; hg19: chr22-25625554;