rs74315487

Positions:

• chr22-26625528-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000354760.4(CRYBA4):​c.206T>C​(p.Leu69Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRYBA4 ENST00000354760.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.22

Genes affected

CRYBA4 (HGNC:2396): (crystallin beta A4) 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 acidic group member, is part of a gene cluster with beta-B1, beta-B2, and beta-B3. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a strand (size 6) in uniprot entity CRBA4_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in ENST00000354760.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 22-26625528-T-C is Pathogenic according to our data. Variant chr22-26625528-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 16947.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-26625528-T-C is described in Lovd as [Pathogenic]. Variant chr22-26625528-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBA4	NM_001886.3	c.206T>C	p.Leu69Pro	missense_variant	4/6	ENST00000354760.4	NP_001877.1
CRYBA4	XM_006724140.4	c.221T>C	p.Leu74Pro	missense_variant	6/8		XP_006724203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBA4	ENST00000354760.4	c.206T>C	p.Leu69Pro	missense_variant	4/6	1	NM_001886.3	ENSP00000346805	P1
CRYBA4	ENST00000466315.1	n.103T>C		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cataract 23 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.97		Gain of disorder (P = 0.0058);
MVP		0.96
MPC		1.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.98
gMVP		0.98

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: rs74315487; hg19: chr22-27021492;