22-26622801-T-C

Variant names:

• chr22-26622801-T-C
• rs79804759
• NM_001886.3:c.39+166T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001886.3(CRYBA4):​c.39+166T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 152,222 control chromosomes in the GnomAD database, including 199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.045 (199 hom., cov: 32)
• Consequence: CRYBA4 NM_001886.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.650
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae), 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 (BayesDel_noAF=-0.94).
• BP6: Variant 22-26622801-T-C is Benign according to our data. Variant chr22-26622801-T-C is described in ClinVar as Benign. ClinVar VariationId is 1281925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0867 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA4	NM_001886.3	MANE Select	c.39+166T>C		intron	N/A	NP_001877.1	A0A097PIJ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA4	ENST00000354760.4	TSL:1 MANE Select	c.39+166T>C		intron	N/A	ENSP00000346805.3	P53673
	CRYBA4	ENST00000466315.1	TSL:5	n.55+166T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6806 AN: 152104 Hom.: 199 Cov.: 32

Gnomad AFR AF: 0.0441

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0365

Gnomad ASJ AF: 0.0531

Gnomad EAS AF: 0.0943

Gnomad SAS AF: 0.0677

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0478

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0448 AC: 6819 AN: 152222 Hom.: 199 Cov.: 32 AF XY: 0.0482 AC XY: 3590 AN XY: 74418

African (AFR) AF: 0.0442 AC: 1838 AN: 41552

American (AMR) AF: 0.0364 AC: 557 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0531 AC: 184 AN: 3468

East Asian (EAS) AF: 0.0936 AC: 484 AN: 5172

South Asian (SAS) AF: 0.0680 AC: 327 AN: 4812

European-Finnish (FIN) AF: 0.103 AC: 1089 AN: 10604

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0325 AC: 2210 AN: 68004

Other (OTH) AF: 0.0511 AC: 108 AN: 2114

Alfa AF: 0.0413 Hom.: 17

Bravo AF: 0.0382

Asia WGS AF: 0.131 AC: 454 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.1
DANN	Benign	0.78
PhyloP100		-0.65
Mutation Taster		=100/0	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: rs79804759; hg19: chr22-27018765; COSMIC: COSV53234816; COSMIC: COSV53234816;