rs9608378

Positions:

• chr22-25205229-C-A
• chr22-25205229-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_004076.5(CRYBB3):​c.337C>A​(p.His113Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 151,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H113D) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 31)
• Consequence: CRYBB3 NM_004076.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.24

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain Beta-crystallin B3 (size 210) in uniprot entity CRBB3_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_004076.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2059347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBB3	NM_004076.5	c.337C>A	p.His113Asn	missense_variant	5/6	ENST00000215855.7	NP_004067.1
CRYBB3	XM_047441147.1	c.337C>A	p.His113Asn	missense_variant	4/5		XP_047297103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB3	ENST00000215855.7	c.337C>A	p.His113Asn	missense_variant	5/6	1	NM_004076.5	ENSP00000215855	P1
CRYBB3	ENST00000404334.1	c.327+1334C>A		intron_variant		3		ENSP00000386123

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151912 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 66

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151912 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74162

Gnomad4 AFR AF: 0.0000726

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.29	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.21
Sift	Benign	0.077	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.23		Gain of sheet (P = 0.0477);
MVP		0.63
MPC		0.16
ClinPred		0.80	D
GERP RS		5.3
Varity_R		0.14
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs9608378; hg19: chr22-25601196;