22-25207157-T-C

Variant names:

• chr22-25207157-T-C
• rs587777601
• NM_004076.5:c.581T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_004076.5(CRYBB3):​c.581T>C​(p.Val194Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V194E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CRYBB3 NM_004076.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.46
• Publications: 0 publications found

Genes affected

CRYBB3 (HGNC:2400): (crystallin beta B3) 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-B2. Mutations in this gene result in cataract congenital nuclear autosomal recessive type 2. [provided by RefSeq, Feb 2013]

CRYBB3 Gene-Disease associations (from GenCC):

• cataract 22 multiple types

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• early-onset anterior polar cataract

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

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a domain Beta/gamma crystallin 'Greek key' 4 (size 42) in uniprot entity CRBB3_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_004076.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-25207157-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 143233.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBB3	NM_004076.5	c.581T>C	p.Val194Ala	missense_variant	Exon 6 of 6	ENST00000215855.7	NP_004067.1
CRYBB3	XM_047441147.1	c.581T>C	p.Val194Ala	missense_variant	Exon 5 of 5		XP_047297103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBB3	ENST00000215855.7	c.581T>C	p.Val194Ala	missense_variant	Exon 6 of 6	1	NM_004076.5	ENSP00000215855.2
CRYBB3	ENST00000404334.1	c.*96T>C		3_prime_UTR_variant	Exon 5 of 5	3		ENSP00000386123.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461378 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727020

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.61
MutPred		0.68		Loss of stability (P = 0.0475);
MVP		0.81
MPC		0.68
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.83
gMVP		0.47
Mutation Taster		=21/79	disease causing

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: rs587777601; hg19: chr22-25603124;