rs9608378

Variant names:

• chr22-25205229-C-G
• rs9608378
• NM_004076.5:c.337C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-25205229-C-G
• chr22-25205229-C-A
• chr22-25205229-C-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.337C>G​(p.His113Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.632 in 1,613,446 control chromosomes in the GnomAD database, including 326,771 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H113Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.59 (27457 hom., cov: 31)
  • Exomes 𝑓: 0.64 (299314 hom.)
• Consequence: CRYBB3 NM_004076.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.24
• Publications: 36 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, G2P, Labcorp Genetics (formerly Invitae)
• 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 (MetaRNN=1.3479986E-6).
• BP6: Variant 22-25205229-C-G is Benign according to our data. Variant chr22-25205229-C-G is described in ClinVar as Benign. ClinVar VariationId is 259229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.911 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB3	NM_004076.5	MANE Select	c.337C>G	p.His113Asp	missense	Exon 5 of 6	NP_004067.1	P26998

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB3	ENST00000215855.7	TSL:1 MANE Select	c.337C>G	p.His113Asp	missense	Exon 5 of 6	ENSP00000215855.2	P26998
	CRYBB3	ENST00000404334.1	TSL:3	c.327+1334C>G		intron	N/A	ENSP00000386123.1	B1AHR5

Frequencies

GnomAD3 genomes AF: 0.593 AC: 89958 AN: 151826 Hom.: 27441 Cov.: 31

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.674

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.934

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.574

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.626

GnomAD2 exomes AF: 0.663 AC: 166523 AN: 251290 AF XY: 0.662

Gnomad AFR exome AF: 0.451

Gnomad AMR exome AF: 0.775

Gnomad ASJ exome AF: 0.681

Gnomad EAS exome AF: 0.930

Gnomad FIN exome AF: 0.584

Gnomad NFE exome AF: 0.622

Gnomad OTH exome AF: 0.666

GnomAD4 exome AF: 0.637 AC: 930251 AN: 1461502 Hom.: 299314 Cov.: 66 AF XY: 0.638 AC XY: 463490 AN XY: 727024

African (AFR) AF: 0.443 AC: 14831 AN: 33466

American (AMR) AF: 0.763 AC: 34097 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 17872 AN: 26128

East Asian (EAS) AF: 0.921 AC: 36550 AN: 39694

South Asian (SAS) AF: 0.681 AC: 58709 AN: 86238

European-Finnish (FIN) AF: 0.587 AC: 31314 AN: 53368

Middle Eastern (MID) AF: 0.640 AC: 3693 AN: 5768

European-Non Finnish (NFE) AF: 0.624 AC: 694196 AN: 1111754

Other (OTH) AF: 0.646 AC: 38989 AN: 60376

GnomAD4 genome AF: 0.592 AC: 90005 AN: 151944 Hom.: 27457 Cov.: 31 AF XY: 0.597 AC XY: 44324 AN XY: 74246

African (AFR) AF: 0.456 AC: 18909 AN: 41436

American (AMR) AF: 0.675 AC: 10307 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 2352 AN: 3472

East Asian (EAS) AF: 0.933 AC: 4798 AN: 5140

South Asian (SAS) AF: 0.698 AC: 3354 AN: 4804

European-Finnish (FIN) AF: 0.574 AC: 6058 AN: 10562

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 42079 AN: 67942

Other (OTH) AF: 0.630 AC: 1328 AN: 2108

Alfa AF: 0.626 Hom.: 21216

Bravo AF: 0.599

TwinsUK AF: 0.627 AC: 2324

ALSPAC AF: 0.619 AC: 2387

ESP6500AA AF: 0.467 AC: 2059

ESP6500EA AF: 0.631 AC: 5425

ExAC AF: 0.656 AC: 79603

Asia WGS AF: 0.806 AC: 2806 AN: 3478

EpiCase AF: 0.625

EpiControl AF: 0.627

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Cataract 22 multiple types (2)
-	-	2	not provided (2)
-	-	1	Congenital nuclear cataract (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.75
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.022	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.8	N
PhyloP100		7.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	4.4	N
REVEL	Benign	0.21
Sift	Benign	0.83	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.059
MPC		0.21
ClinPred		0.0085	T
GERP RS		5.3
Varity_R		0.14
gMVP		0.44
Mutation Taster		=67/33	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs9608378; hg19: chr22-25601196; COSMIC: COSV53194229;