22-26623300-G-A

Variant names:

• chr22-26623300-G-A
• rs35520672
• NM_001886.3:c.106G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001886.3(CRYBA4):​c.106G>A​(p.Val36Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,614,012 control chromosomes in the GnomAD database, including 411 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V36V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (27 hom., cov: 32)
  • Exomes 𝑓: 0.021 (384 hom.)
• Consequence: CRYBA4 NM_001886.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.39
• Publications: 8 publications found

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]

CRYBA4 Gene-Disease associations (from GenCC):

• cataract 23

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• cataract - microcornea syndrome

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030172765).
• BP6: Variant 22-26623300-G-A is Benign according to our data. Variant chr22-26623300-G-A is described in ClinVar as Benign. ClinVar VariationId is 258485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2532/152278) while in subpopulation NFE AF = 0.025 (1703/68032). AF 95% confidence interval is 0.024. There are 27 homozygotes in GnomAd4. There are 1220 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001886.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA4	NM_001886.3	MANE Select	c.106G>A	p.Val36Met	missense	Exon 3 of 6	NP_001877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA4	ENST00000354760.4	TSL:1 MANE Select	c.106G>A	p.Val36Met	missense	Exon 3 of 6	ENSP00000346805.3
	CRYBA4	ENST00000466315.1	TSL:5	n.55+665G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2531 AN: 152162 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00471

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.0433

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0174 AC: 4372 AN: 251340 AF XY: 0.0180

Gnomad AFR exome AF: 0.00492

Gnomad AMR exome AF: 0.00728

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0437

Gnomad NFE exome AF: 0.0250

Gnomad OTH exome AF: 0.0169

GnomAD4 exome AF: 0.0212 AC: 30922 AN: 1461734 Hom.: 384 Cov.: 32 AF XY: 0.0208 AC XY: 15138 AN XY: 727190

African (AFR) AF: 0.00320 AC: 107 AN: 33480

American (AMR) AF: 0.00745 AC: 333 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00578 AC: 151 AN: 26136

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

South Asian (SAS) AF: 0.00436 AC: 376 AN: 86258

European-Finnish (FIN) AF: 0.0409 AC: 2181 AN: 53304

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5766

European-Non Finnish (NFE) AF: 0.0241 AC: 26802 AN: 1111978

Other (OTH) AF: 0.0151 AC: 914 AN: 60388

GnomAD4 genome AF: 0.0166 AC: 2532 AN: 152278 Hom.: 27 Cov.: 32 AF XY: 0.0164 AC XY: 1220 AN XY: 74456

African (AFR) AF: 0.00470 AC: 195 AN: 41532

American (AMR) AF: 0.00699 AC: 107 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4830

European-Finnish (FIN) AF: 0.0433 AC: 459 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0250 AC: 1703 AN: 68032

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.0211 Hom.: 143

Bravo AF: 0.0139

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.0248 AC: 213

ExAC AF: 0.0173 AC: 2100

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0248

EpiControl AF: 0.0274

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 22, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cataract 23 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.22
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.16
MPC		0.88
ClinPred		0.015	T
GERP RS		3.4
Varity_R		0.40
gMVP		0.57
Mutation Taster		=95/5	polymorphism (auto)

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: rs35520672; hg19: chr22-27019264; COSMIC: COSV99081169;