rs864309697

Positions:

• chr22-25229472-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000496.3(CRYBB2):​c.343C>A​(p.Pro115Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRYBB2 NM_000496.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.90

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain Beta/gamma crystallin 'Greek key' 3 (size 41) in uniprot entity CRBB2_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000496.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBB2	NM_000496.3	c.343C>A	p.Pro115Thr	missense_variant	5/6	ENST00000398215.3	NP_000487.1
CRYBB2	XM_006724141.4	c.343C>A	p.Pro115Thr	missense_variant	5/6		XP_006724204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB2	ENST00000398215.3	c.343C>A	p.Pro115Thr	missense_variant	5/6	1	NM_000496.3	ENSP00000381273	P1
CRYBB2	ENST00000651629.1	c.343C>A	p.Pro115Thr	missense_variant	5/6			ENSP00000498905	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.044
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.47
Sift	Benign	0.47	T
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.79
MutPred		0.47		Gain of sheet (P = 0.0827);
MVP		0.77
MPC		0.55
ClinPred		0.77	D
GERP RS		4.7
Varity_R		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs864309697; hg19: chr22-25625439;