22-25201364-T-C

Variant names:

• chr22-25201364-T-C
• rs2269672
• NM_004076.5:c.-20-13T>C

Variant summary

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

The NM_004076.5(CRYBB3):​c.-20-13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 1,611,378 control chromosomes in the GnomAD database, including 238,312 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28865 hom., cov: 32)
  • Exomes 𝑓: 0.53 (209447 hom.)
• Consequence: CRYBB3 NM_004076.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.341
• Publications: 23 publications found

Genes affected

CRYBB3 (HGNC:2400): (crystallin beta B3) 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-B2. Mutations in this gene result in cataract congenital nuclear autosomal recessive type 2. [provided by RefSeq, Feb 2013]

CRYBB3 Gene-Disease associations (from GenCC):

• cataract 22 multiple types

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• early-onset anterior polar cataract

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

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 22-25201364-T-C is Benign according to our data. Variant chr22-25201364-T-C is described in ClinVar as Benign. ClinVar VariationId is 340947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004076.5. 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
	CRYBB3	NM_004076.5	MANE Select	c.-20-13T>C		intron	N/A	NP_004067.1	P26998

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB3	ENST00000215855.7	TSL:1 MANE Select	c.-20-13T>C		intron	N/A	ENSP00000215855.2	P26998
	CRYBB3	ENST00000404334.1	TSL:3	c.-16-17T>C		intron	N/A	ENSP00000386123.1	B1AHR5

Frequencies

GnomAD3 genomes AF: 0.603 AC: 91641 AN: 151984 Hom.: 28801 Cov.: 32

Gnomad AFR AF: 0.787

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.595

GnomAD2 exomes AF: 0.564 AC: 141604 AN: 251264 AF XY: 0.553

Gnomad AFR exome AF: 0.788

Gnomad AMR exome AF: 0.647

Gnomad ASJ exome AF: 0.565

Gnomad EAS exome AF: 0.683

Gnomad FIN exome AF: 0.472

Gnomad NFE exome AF: 0.514

Gnomad OTH exome AF: 0.560

GnomAD4 exome AF: 0.532 AC: 777059 AN: 1459276 Hom.: 209447 Cov.: 107 AF XY: 0.531 AC XY: 385342 AN XY: 725938

African (AFR) AF: 0.800 AC: 26724 AN: 33424

American (AMR) AF: 0.641 AC: 28627 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 14828 AN: 26068

East Asian (EAS) AF: 0.660 AC: 26134 AN: 39570

South Asian (SAS) AF: 0.523 AC: 45063 AN: 86142

European-Finnish (FIN) AF: 0.471 AC: 25020 AN: 53112

Middle Eastern (MID) AF: 0.530 AC: 3042 AN: 5744

European-Non Finnish (NFE) AF: 0.517 AC: 574093 AN: 1110382

Other (OTH) AF: 0.557 AC: 33528 AN: 60204

GnomAD4 genome AF: 0.603 AC: 91761 AN: 152102 Hom.: 28865 Cov.: 32 AF XY: 0.602 AC XY: 44781 AN XY: 74350

African (AFR) AF: 0.788 AC: 32705 AN: 41510

American (AMR) AF: 0.598 AC: 9154 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1954 AN: 3470

East Asian (EAS) AF: 0.684 AC: 3535 AN: 5166

South Asian (SAS) AF: 0.536 AC: 2583 AN: 4822

European-Finnish (FIN) AF: 0.469 AC: 4961 AN: 10568

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.515 AC: 34977 AN: 67954

Other (OTH) AF: 0.600 AC: 1265 AN: 2108

Alfa AF: 0.544 Hom.: 34815

Bravo AF: 0.628

Asia WGS AF: 0.645 AC: 2244 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cataract 22 multiple types (1)
-	-	1	Congenital nuclear cataract (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	8.8
DANN	Benign	0.59
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2269672; hg19: chr22-25597331; COSMIC: COSV53194219; COSMIC: COSV53194219;