rs56191632

Variant names:

• chr22-25221587-G-C
• rs56191632
• NM_000496.3:c.54+104G>C

Your query was ambiguous. Multiple possible variants found:

• chr22-25221587-G-C
• chr22-25221587-G-A

Variant summary

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

The NM_000496.3(CRYBB2):​c.54+104G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.044 in 815,004 control chromosomes in the GnomAD database, including 912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (154 hom., cov: 32)
  • Exomes 𝑓: 0.044 (758 hom.)
• Consequence: CRYBB2 NM_000496.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.64
• Publications: 2 publications found

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]

CRYBB2 Gene-Disease associations (from GenCC):

• cataract 3 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• cataract - microcornea syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cerulean cataract

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

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulverulent cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset 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=-0.93).
• BP6: Variant 22-25221587-G-C is Benign according to our data. Variant chr22-25221587-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1191251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0845 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000496.3. 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
	CRYBB2	NM_000496.3	MANE Select	c.54+104G>C		intron	N/A	NP_000487.1	P43320

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB2	ENST00000398215.3	TSL:1 MANE Select	c.54+104G>C		intron	N/A	ENSP00000381273.2	P43320
	CRYBB2	ENST00000651629.1		c.54+104G>C		intron	N/A	ENSP00000498905.1	P43320
	CRYBB2	ENST00000855619.1		c.54+104G>C		intron	N/A	ENSP00000525678.1

Frequencies

GnomAD3 genomes AF: 0.0423 AC: 6438 AN: 152082 Hom.: 153 Cov.: 32

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0371

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0909

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.0489

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0505

Gnomad OTH AF: 0.0378

GnomAD4 exome AF: 0.0444 AC: 29419 AN: 662804 Hom.: 758 AF XY: 0.0430 AC XY: 15192 AN XY: 352962

African (AFR) AF: 0.0290 AC: 522 AN: 18016

American (AMR) AF: 0.0305 AC: 1088 AN: 35622

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 456 AN: 19848

East Asian (EAS) AF: 0.0777 AC: 2559 AN: 32932

South Asian (SAS) AF: 0.0126 AC: 820 AN: 65014

European-Finnish (FIN) AF: 0.0495 AC: 2205 AN: 44512

Middle Eastern (MID) AF: 0.0186 AC: 78 AN: 4188

European-Non Finnish (NFE) AF: 0.0495 AC: 20245 AN: 408948

Other (OTH) AF: 0.0429 AC: 1446 AN: 33724

GnomAD4 genome AF: 0.0423 AC: 6445 AN: 152200 Hom.: 154 Cov.: 32 AF XY: 0.0417 AC XY: 3099 AN XY: 74396

African (AFR) AF: 0.0278 AC: 1153 AN: 41532

American (AMR) AF: 0.0370 AC: 565 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3472

East Asian (EAS) AF: 0.0913 AC: 472 AN: 5170

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4820

European-Finnish (FIN) AF: 0.0489 AC: 518 AN: 10586

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

European-Non Finnish (NFE) AF: 0.0505 AC: 3432 AN: 68018

Other (OTH) AF: 0.0374 AC: 79 AN: 2112

Alfa AF: 0.0147 Hom.: 8

Bravo AF: 0.0419

Asia WGS AF: 0.0380 AC: 133 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely 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	-0.93
CADD	Benign	0.020
DANN	Benign	0.44
PhyloP100		-1.6
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: rs56191632; hg19: chr22-25617554; COSMIC: COSV107506259;