rs370450145

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_005210.4(CRYGB):​c.44G>A​(p.Arg15His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,614,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

CRYGB
NM_005210.4 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.966
Variant links:
Genes affected
CRYGB (HGNC:2409): (crystallin gamma B) 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. Gamma-crystallins are a homogeneous group of highly symmetrical, monomeric proteins typically lacking connecting peptides and terminal extensions. They are differentially regulated after early development. Four gamma-crystallin genes (gamma-A through gamma-D) and three pseudogenes (gamma-E, gamma-F, gamma-G) are tandemly organized in a genomic segment as a gene cluster. Whether due to aging or mutations in specific genes, gamma-crystallins have been involved in cataract formation. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.35962132).
BS2
High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CRYGBNM_005210.4 linkuse as main transcriptc.44G>A p.Arg15His missense_variant 2/3 ENST00000260988.5 NP_005201.2 P07316
CRYGBXM_017003402.2 linkuse as main transcriptc.44G>A p.Arg15His missense_variant 2/3 XP_016858891.1
LOC100507443NR_038437.1 linkuse as main transcriptn.221+8803C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CRYGBENST00000260988.5 linkuse as main transcriptc.44G>A p.Arg15His missense_variant 2/31 NM_005210.4 ENSP00000260988.4 P07316

Frequencies

GnomAD3 genomes
AF:
0.0000986
AC:
15
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
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:
0.000956
GnomAD3 exomes
AF:
0.0000597
AC:
15
AN:
251438
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135898
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000383
AC:
56
AN:
1461892
Hom.:
0
Cov.:
61
AF XY:
0.0000358
AC XY:
26
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.000168
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.0000985
AC:
15
AN:
152300
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.000168
Gnomad4 AMR
AF:
0.000392
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:
0.000946
Alfa
AF:
0.0000847
Hom.:
0
Bravo
AF:
0.000140
ExAC
AF:
0.0000330
AC:
4
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cataract 39 multiple types Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 15 of the CRYGB protein (p.Arg15His). This variant is present in population databases (rs370450145, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CRYGB-related conditions. ClinVar contains an entry for this variant (Variation ID: 572782). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.55
D
Eigen
Benign
-0.41
Eigen_PC
Benign
-0.38
FATHMM_MKL
Benign
0.39
N
LIST_S2
Uncertain
0.97
D
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.36
T
MetaSVM
Benign
-0.63
T
MutationAssessor
Uncertain
2.2
M
PrimateAI
Benign
0.31
T
PROVEAN
Uncertain
-3.6
D
REVEL
Uncertain
0.29
Sift
Benign
0.11
T
Sift4G
Benign
0.088
T
Polyphen
0.071
B
Vest4
0.27
MutPred
0.82
Loss of solvent accessibility (P = 0.239);
MVP
0.70
MPC
0.070
ClinPred
0.15
T
GERP RS
2.8
Varity_R
0.33
gMVP
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs370450145; hg19: chr2-209010706; API