22-25221469-T-A

Position:

• chr22-25221469-T-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000496.3(CRYBB2):​c.40T>A​(p.Ser14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,613,458 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (108 hom.)
• Consequence: CRYBB2 NM_000496.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.75

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 Benign. Variant got -18 ACMG points.

• PM1: In a chain Beta-crystallin B2 (size 203) in uniprot entity CRBB2_HUMAN there are 36 pathogenic changes around while only 2 benign (95%) in NM_000496.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017588735).
• BP6: Variant 22-25221469-T-A is Benign according to our data. Variant chr22-25221469-T-A is described in ClinVar as [Benign]. Clinvar id is 667923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBB2	NM_000496.3	c.40T>A	p.Ser14Thr	missense_variant	2/6	ENST00000398215.3
CRYBB2	XM_006724141.4	c.40T>A	p.Ser14Thr	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBB2	ENST00000398215.3	c.40T>A	p.Ser14Thr	missense_variant	2/6	1	NM_000496.3	P1
CRYBB2	ENST00000651629.1	c.40T>A	p.Ser14Thr	missense_variant	2/6			P1

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 450 AN: 152138 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0732

Gnomad SAS AF: 0.00229

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00581 AC: 1459 AN: 251280 Hom.: 58 AF XY: 0.00564 AC XY: 766 AN XY: 135842

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0762

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00212 AC: 3101 AN: 1461202 Hom.: 108 Cov.: 30 AF XY: 0.00214 AC XY: 1558 AN XY: 726958

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0692

Gnomad4 SAS exome AF: 0.000916

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome AF: 0.00296 AC: 451 AN: 152256 Hom.: 20 Cov.: 32 AF XY: 0.00322 AC XY: 240 AN XY: 74436

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0730

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00255 Hom.: 6

Bravo AF: 0.00280

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00532 AC: 646

Asia WGS AF: 0.0200 AC: 69 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 3 multiple types Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 16, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.42	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.068
Sift	Benign	0.46	T
Sift4G	Benign	0.74	T
Polyphen		0.0010	B
Vest4		0.092
MVP		0.43
MPC		0.42
ClinPred		0.0039	T
GERP RS		1.6
Varity_R		0.050

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: rs117457580; hg19: chr22-25617436;