rs4049507

Positions:

• chr22-25229682-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000398215.3(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 ENST00000398215.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.874

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]

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 126 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBB2	NM_000496.3	c.449+104G>A		intron_variant		ENST00000398215.3	NP_000487.1
CRYBB2	XM_006724141.4	c.449+104G>A		intron_variant			XP_006724204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB2	ENST00000398215.3	c.449+104G>A		intron_variant		1	NM_000496.3	ENSP00000381273	P1
CRYBB2	ENST00000651629.1	c.449+104G>A		intron_variant				ENSP00000498905	P1

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

Gnomad4 AFR exome AF: 0.00118

Gnomad4 AMR exome AF: 0.00137

Gnomad4 ASJ exome AF: 0.00491

Gnomad4 EAS exome AF: 0.000162

Gnomad4 SAS exome AF: 0.000913

Gnomad4 FIN exome AF: 0.0000975

Gnomad4 NFE exome AF: 0.000351

Gnomad4 OTH exome AF: 0.000647

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

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000971 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.19
DANN	Benign	0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs4049507; hg19: chr22-25625649;