22-25225036-C-T

Variant names:

• chr22-25225036-C-T
• rs763268420
• NM_000496.3:c.173C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PP2 PP3 PP5_Moderate BS2_Supporting

The NM_000496.3(CRYBB2):​c.173C>T​(p.Pro58Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000571 in 1,400,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: CRYBB2 NM_000496.3 missense, splice_region
• Scores: Splicing: ADA: 0.9863
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.50
• Publications: 3 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: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a chain Beta-crystallin B2 (size 203) in uniprot entity CRBB2_HUMAN there are 13 pathogenic changes around while only 4 benign (76%) in NM_000496.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.0723 (below the threshold of 3.09). Trascript score misZ: 1.7369 (below the threshold of 3.09). GenCC associations: The gene is linked to cataract 3 multiple types, pulverulent cataract, cataract - microcornea syndrome, early-onset posterior subcapsular cataract, total early-onset cataract, early-onset nuclear cataract, cerulean cataract, early-onset sutural cataract.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 22-25225036-C-T is Pathogenic according to our data. Variant chr22-25225036-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1210343.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB2	NM_000496.3	MANE Select	c.173C>T	p.Pro58Leu	missense splice_region	Exon 3 of 6	NP_000487.1	P43320

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB2	ENST00000398215.3	TSL:1 MANE Select	c.173C>T	p.Pro58Leu	missense splice_region	Exon 3 of 6	ENSP00000381273.2	P43320
	CRYBB2	ENST00000651629.1		c.173C>T	p.Pro58Leu	missense splice_region	Exon 3 of 6	ENSP00000498905.1	P43320
	CRYBB2	ENST00000855619.1		c.173C>T	p.Pro58Leu	missense splice_region	Exon 2 of 5	ENSP00000525678.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251380 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000571 AC: 8 AN: 1400090 Hom.: 0 Cov.: 25 AF XY: 0.00000571 AC XY: 4 AN XY: 700404

African (AFR) AF: 0.0000311 AC: 1 AN: 32198

American (AMR) AF: 0.00 AC: 0 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25750

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 85074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00000474 AC: 5 AN: 1055618

Other (OTH) AF: 0.0000171 AC: 1 AN: 58334

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cataract 3 multiple types (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.0086	D
MutationAssessor	Benign	1.5	L
PhyloP100		4.5
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.68		Gain of sheet (P = 0.0827)
MVP		0.52
MPC		1.3
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.92
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.81
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: rs763268420; hg19: chr22-25621003;