chr22-25207041-C-T

Variant names:

• chr22-25207041-C-T
• rs13055430
• NM_004076.5:c.471-6C>T

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.471-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0824 in 1,610,468 control chromosomes in the GnomAD database, including 6,212 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (396 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5816 hom.)
• Consequence: CRYBB3 NM_004076.5 splice_region, intron
• Scores: Splicing: ADA: 0.0004944
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0380
• Publications: 6 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, AD, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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=-0.57).
• BP6: Variant 22-25207041-C-T is Benign according to our data. Variant chr22-25207041-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB3	NM_004076.5	MANE Select	c.471-6C>T		splice_region intron	N/A	NP_004067.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB3	ENST00000215855.7	TSL:1 MANE Select	c.471-6C>T		splice_region intron	N/A	ENSP00000215855.2
	CRYBB3	ENST00000404334.1	TSL:3	c.328-6C>T		splice_region intron	N/A	ENSP00000386123.1

Frequencies

GnomAD3 genomes AF: 0.0652 AC: 9919 AN: 152094 Hom.: 394 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0462

Gnomad ASJ AF: 0.0732

Gnomad EAS AF: 0.0292

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0855

Gnomad OTH AF: 0.0522

GnomAD2 exomes AF: 0.0798 AC: 19874 AN: 249134 AF XY: 0.0846

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.0430

Gnomad ASJ exome AF: 0.0720

Gnomad EAS exome AF: 0.0317

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.0852

Gnomad OTH exome AF: 0.0788

GnomAD4 exome AF: 0.0842 AC: 122807 AN: 1458256 Hom.: 5816 Cov.: 30 AF XY: 0.0865 AC XY: 62804 AN XY: 725714

African (AFR) AF: 0.0193 AC: 644 AN: 33410

American (AMR) AF: 0.0415 AC: 1856 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0710 AC: 1853 AN: 26114

East Asian (EAS) AF: 0.0209 AC: 829 AN: 39692

South Asian (SAS) AF: 0.141 AC: 12163 AN: 86202

European-Finnish (FIN) AF: 0.115 AC: 6113 AN: 53196

Middle Eastern (MID) AF: 0.0529 AC: 305 AN: 5766

European-Non Finnish (NFE) AF: 0.0847 AC: 93908 AN: 1108864

Other (OTH) AF: 0.0852 AC: 5136 AN: 60292

GnomAD4 genome AF: 0.0652 AC: 9930 AN: 152212 Hom.: 396 Cov.: 32 AF XY: 0.0669 AC XY: 4977 AN XY: 74418

African (AFR) AF: 0.0221 AC: 919 AN: 41554

American (AMR) AF: 0.0463 AC: 708 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0732 AC: 254 AN: 3472

East Asian (EAS) AF: 0.0290 AC: 150 AN: 5164

South Asian (SAS) AF: 0.150 AC: 726 AN: 4828

European-Finnish (FIN) AF: 0.112 AC: 1187 AN: 10592

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0855 AC: 5816 AN: 67992

Other (OTH) AF: 0.0550 AC: 116 AN: 2110

Alfa AF: 0.0746 Hom.: 455

Bravo AF: 0.0558

Asia WGS AF: 0.100 AC: 348 AN: 3478

EpiCase AF: 0.0807

EpiControl AF: 0.0755

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.86
PhyloP100		-0.038
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00049
dbscSNV1_RF	Benign	0.028
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: rs13055430; hg19: chr22-25603008; COSMIC: COSV53194652;