rs969623

Variant names:

• chr22-25220246-T-C
• rs969623
• NM_000496.3:c.-27+580T>C

Your query was ambiguous. Multiple possible variants found:

• chr22-25220246-T-C
• chr22-25220246-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000496.3(CRYBB2):​c.-27+580T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 152,112 control chromosomes in the GnomAD database, including 9,242 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 0.32 (9242 hom., cov: 33)
• Consequence: CRYBB2 NM_000496.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660
• Publications: 8 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• 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).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBB2	NM_000496.3	c.-27+580T>C		intron_variant	Intron 1 of 5	ENST00000398215.3	NP_000487.1
CRYBB2	XM_006724141.4	c.-26-1158T>C		intron_variant	Intron 1 of 5		XP_006724204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBB2	ENST00000398215.3	c.-27+580T>C		intron_variant	Intron 1 of 5	1	NM_000496.3	ENSP00000381273.2
CRYBB2	ENST00000651629.1	c.-26-1158T>C		intron_variant	Intron 1 of 5			ENSP00000498905.1

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49219 AN: 151994 Hom.: 9238 Cov.: 33

Gnomad AFR AF: 0.524

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.308

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.324 AC: 49269 AN: 152112 Hom.: 9242 Cov.: 33 AF XY: 0.323 AC XY: 24018 AN XY: 74372

African (AFR) AF: 0.524 AC: 21719 AN: 41458

American (AMR) AF: 0.279 AC: 4262 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 867 AN: 3466

East Asian (EAS) AF: 0.324 AC: 1677 AN: 5172

South Asian (SAS) AF: 0.334 AC: 1609 AN: 4820

European-Finnish (FIN) AF: 0.227 AC: 2410 AN: 10594

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15723 AN: 67996

Other (OTH) AF: 0.312 AC: 659 AN: 2112

Alfa AF: 0.262 Hom.: 22797

Bravo AF: 0.340

Asia WGS AF: 0.327 AC: 1135 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.7
DANN	Benign	0.45
PhyloP100		-0.066
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: rs969623; hg19: chr22-25616213;