22-26602004-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001887.4(CRYBB1):c.450A>T(p.Lys150Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,461,588 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K150E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CRYBB1 NM_001887.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

Genes affected

CRYBB1 (HGNC:2397): (crystallin beta B1) 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, undergoes extensive cleavage at its N-terminal extension during lens maturation. It is also a member of a gene cluster with beta-A4, beta-B2, and beta-B3. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBB1	NM_001887.4	c.450A>T	p.Lys150Asn	missense_variant	5/6	ENST00000647684.1
CRYBB1	XM_011529899.4	c.450A>T	p.Lys150Asn	missense_variant	5/6
CRYBA4	XM_006724140.4	c.-239+4921T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBB1	ENST00000647684.1	c.450A>T	p.Lys150Asn	missense_variant	5/6		NM_001887.4	P1
	ENST00000668614.1	n.56+4921T>A		intron_variant, non_coding_transcript_variant
CRYBB1	ENST00000647569.1	n.262A>T		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461588 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000942 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.450A>T (p.K150N) alteration is located in exon 5 (coding exon 4) of the CRYBB1 gene. This alteration results from a A to T substitution at nucleotide position 450, causing the lysine (K) at amino acid position 150 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
Polyphen		0.98	D;D
Vest4		0.87
MutPred		0.63		Loss of ubiquitination at K150 (P = 0.0199);Loss of ubiquitination at K150 (P = 0.0199);
MVP		0.89
MPC		0.99
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.87
gMVP		0.77

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: rs1928836276; hg19: chr22-26997968;