rs147206089

Positions:

• chr22-26607993-G-A
• chr22-26607993-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001887.4(CRYBB1):​c.328C>T​(p.Arg110Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,614,210 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (32 hom.)
• Consequence: CRYBB1 NM_001887.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.08

Genes affected

CRYBB1 (HGNC:2397): (crystallin beta B1) 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, undergoes extensive cleavage at its N-terminal extension during lens maturation. It is also a member of a gene cluster with beta-A4, beta-B2, and beta-B3. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01889366).
• BP6: Variant 22-26607993-G-A is Benign according to our data. Variant chr22-26607993-G-A is described in ClinVar as [Benign]. Clinvar id is 468742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-26607993-G-A is described in Lovd as [Likely_benign]. Variant chr22-26607993-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00247 (376/152346) while in subpopulation SAS AF= 0.00807 (39/4834). AF 95% confidence interval is 0.00607. There are 2 homozygotes in gnomad4. There are 181 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBB1	NM_001887.4	c.328C>T	p.Arg110Cys	missense_variant	4/6	ENST00000647684.1
CRYBB1	XM_011529899.4	c.328C>T	p.Arg110Cys	missense_variant	4/6
CRYBA4	XM_006724140.4	c.-67G>A		5_prime_UTR_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBB1	ENST00000647684.1	c.328C>T	p.Arg110Cys	missense_variant	4/6		NM_001887.4	P1
	ENST00000668614.1	n.228G>A		non_coding_transcript_exon_variant	2/3
CRYBB1	ENST00000647569.1	n.140C>T		non_coding_transcript_exon_variant	2/3

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 372 AN: 152228 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00379

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00382 AC: 961 AN: 251424 Hom.: 9 AF XY: 0.00467 AC XY: 635 AN XY: 135898

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00942

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0127

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00346

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00378 AC: 5531 AN: 1461864 Hom.: 32 Cov.: 32 AF XY: 0.00419 AC XY: 3050 AN XY: 727232

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00742

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0125

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.00347

Gnomad4 OTH exome AF: 0.00376

GnomAD4 genome AF: 0.00247 AC: 376 AN: 152346 Hom.: 2 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74502

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00807

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00381

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00357 Hom.: 1

Bravo AF: 0.00241

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00396 AC: 481

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CRYBB1: BP4, BS1, BS2; ENSG00000286326: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Cataract 17 multiple types Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2023	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Benign	0.30	T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	.;D
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.7	.;D
REVEL	Uncertain	0.31
Sift	Benign	0.30	.;T
Sift4G	Benign	0.33	.;T
Polyphen		0.11	B;B
Vest4		0.56
MVP		0.86
MPC		0.44
ClinPred		0.0095	T
GERP RS		2.5
Varity_R		0.23
gMVP		0.71

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: rs147206089; hg19: chr22-27003957;