rs16986560

Variant names:

• chr22-25227872-G-T
• rs16986560
• NM_000496.3:c.193G>T

Your query was ambiguous. Multiple possible variants found:

• chr22-25227872-G-T
• chr22-25227872-G-A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000496.3(CRYBB2):​c.193G>T​(p.Ala65Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,614,088 control chromosomes in the GnomAD database, including 285 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (24 hom., cov: 28)
  • Exomes 𝑓: 0.013 (261 hom.)
• Consequence: CRYBB2 NM_000496.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.80
• Publications: 9 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: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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 -17 ACMG points.

• PM1: In a chain Beta-crystallin B2 (size 203) in uniprot entity CRBB2_HUMAN there are 13 pathogenic changes around while only 4 benign (76%) in NM_000496.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.0723 (below the threshold of 3.09). Trascript score misZ: 1.7369 (below the threshold of 3.09). GenCC associations: The gene is linked to cataract - microcornea syndrome, cataract 3 multiple types, total early-onset cataract, pulverulent cataract, early-onset posterior subcapsular cataract, early-onset sutural cataract, cerulean cataract, early-onset nuclear cataract.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0042724013).
• BP6: Variant 22-25227872-G-T is Benign according to our data. Variant chr22-25227872-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0161 (2446/152218) while in subpopulation SAS AF = 0.044 (212/4820). AF 95% confidence interval is 0.0391. There are 24 homozygotes in GnomAd4. There are 1210 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2446 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000496.3. 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
	CRYBB2	NM_000496.3	MANE Select	c.193G>T	p.Ala65Ser	missense	Exon 4 of 6	NP_000487.1	P43320

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBB2	ENST00000398215.3	TSL:1 MANE Select	c.193G>T	p.Ala65Ser	missense	Exon 4 of 6	ENSP00000381273.2	P43320
	CRYBB2	ENST00000651629.1		c.193G>T	p.Ala65Ser	missense	Exon 4 of 6	ENSP00000498905.1	P43320
	CRYBB2	ENST00000855619.1		c.193G>T	p.Ala65Ser	missense	Exon 3 of 5	ENSP00000525678.1

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2436 AN: 152100 Hom.: 22 Cov.: 28

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.0435

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0163 AC: 4108 AN: 251372 AF XY: 0.0177

Gnomad AFR exome AF: 0.0277

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.0135

Gnomad FIN exome AF: 0.0212

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0131 AC: 19158 AN: 1461870 Hom.: 261 Cov.: 32 AF XY: 0.0143 AC XY: 10399 AN XY: 727236

African (AFR) AF: 0.0231 AC: 774 AN: 33480

American (AMR) AF: 0.00347 AC: 155 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00570 AC: 149 AN: 26136

East Asian (EAS) AF: 0.00741 AC: 294 AN: 39700

South Asian (SAS) AF: 0.0467 AC: 4025 AN: 86258

European-Finnish (FIN) AF: 0.0211 AC: 1129 AN: 53398

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.0106 AC: 11732 AN: 1112010

Other (OTH) AF: 0.0144 AC: 867 AN: 60396

GnomAD4 genome AF: 0.0161 AC: 2446 AN: 152218 Hom.: 24 Cov.: 28 AF XY: 0.0163 AC XY: 1210 AN XY: 74420

African (AFR) AF: 0.0255 AC: 1059 AN: 41524

American (AMR) AF: 0.00477 AC: 73 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.0103 AC: 53 AN: 5170

South Asian (SAS) AF: 0.0440 AC: 212 AN: 4820

European-Finnish (FIN) AF: 0.0214 AC: 227 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0109 AC: 743 AN: 68018

Other (OTH) AF: 0.0171 AC: 36 AN: 2104

Alfa AF: 0.0120 Hom.: 19

Bravo AF: 0.0147

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.0309 AC: 136

ESP6500EA AF: 0.00919 AC: 79

ExAC AF: 0.0173 AC: 2105

Asia WGS AF: 0.0560 AC: 195 AN: 3478

EpiCase AF: 0.00867

EpiControl AF: 0.00895

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Benign	0.81
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.0037
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.41	N
PhyloP100		1.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.13
Sift	Benign	0.76	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.13
MPC		0.42
ClinPred		0.0030	T
GERP RS		4.1
Varity_R		0.16
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs16986560; hg19: chr22-25623839; COSMIC: COSV68005481;