rs4049507

Variant names:

• chr22-25229682-G-A
• rs4049507
• NM_000496.3:c.449+104G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000496.3(CRYBB2):​c.449+104G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000565 in 1,525,260 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00054 (2 hom.)
• Consequence: CRYBB2 NM_000496.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.874
• Publications: 1 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: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000827 (126/152362) while in subpopulation AFR AF = 0.00144 (60/41586). AF 95% confidence interval is 0.00115. There are 0 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 126 AD gene.

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.449+104G>A		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.449+104G>A		intron	N/A	ENSP00000381273.2	P43320
	CRYBB2	ENST00000651629.1		c.449+104G>A		intron	N/A	ENSP00000498905.1	P43320
	CRYBB2	ENST00000855619.1		c.449+104G>A		intron	N/A	ENSP00000525678.1

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152244 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.000536 AC: 736 AN: 1372898 Hom.: 2 AF XY: 0.000508 AC XY: 346 AN XY: 681350

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00118 AC: 37 AN: 31356

American (AMR) AF: 0.00137 AC: 52 AN: 37978

Ashkenazi Jewish (ASJ) AF: 0.00491 AC: 122 AN: 24872

East Asian (EAS) AF: 0.000162 AC: 6 AN: 37052

South Asian (SAS) AF: 0.000913 AC: 73 AN: 79936

European-Finnish (FIN) AF: 0.0000975 AC: 5 AN: 51258

Middle Eastern (MID) AF: 0.00691 AC: 36 AN: 5208

European-Non Finnish (NFE) AF: 0.000351 AC: 368 AN: 1048060

Other (OTH) AF: 0.000647 AC: 37 AN: 57178

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000827 AC: 126 AN: 152362 Hom.: 0 Cov.: 31 AF XY: 0.000805 AC XY: 60 AN XY: 74508

African (AFR) AF: 0.00144 AC: 60 AN: 41586

American (AMR) AF: 0.00118 AC: 18 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68036

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000971 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.19
DANN	Benign	0.38
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism

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: rs4049507; hg19: chr22-25625649;