rs28931604

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_020989.4(CRYGC):​c.502C>T​(p.Arg168Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000671 in 1,614,202 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R168Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00033 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00071 ( 18 hom. )

Consequence

CRYGC
NM_020989.4 missense

Scores

6
4
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.0780
Variant links:
Genes affected
CRYGC (HGNC:2410): (crystallin gamma C) This gene encodes a member of the beta/gamma-crystallin family of proteins. Crystallins constitute the major proteins of vertebrate eye lens and maintain the transparency and refractive index of the lens. This gene and several family members are present in a gene cluster on chromosome 2. Mutations in this gene have been shown to cause multiple types of cataract, including Coppock-like cataract and zonular pulverulent cataract, among others. [provided by RefSeq, Jan 2015]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM1
In a domain Beta/gamma crystallin 'Greek key' 4 (size 42) in uniprot entity CRGC_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_020989.4
BP4
Computational evidence support a benign effect (MetaRNN=0.023029655).
BS2
High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CRYGCNM_020989.4 linkc.502C>T p.Arg168Trp missense_variant Exon 3 of 3 ENST00000282141.4 NP_066269.1 P07315A0A0X8GLL6
LOC100507443NR_038437.1 linkn.98-8830G>A intron_variant Intron 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CRYGCENST00000282141.4 linkc.502C>T p.Arg168Trp missense_variant Exon 3 of 3 1 NM_020989.4 ENSP00000282141.3 P07315

Frequencies

GnomAD3 genomes
AF:
0.000329
AC:
50
AN:
152190
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00911
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00158
AC:
396
AN:
251426
AF XY:
0.00204
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000723
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.000815
GnomAD4 exome
AF:
0.000707
AC:
1033
AN:
1461894
Hom.:
18
Cov.:
31
AF XY:
0.00101
AC XY:
737
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
AC:
1
AN:
33480
Gnomad4 AMR exome
AF:
0.000648
AC:
29
AN:
44724
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26136
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39700
Gnomad4 SAS exome
AF:
0.0110
AC:
952
AN:
86258
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53420
Gnomad4 NFE exome
AF:
0.0000126
AC:
14
AN:
1112012
Gnomad4 Remaining exome
AF:
0.000596
AC:
36
AN:
60396
Heterozygous variant carriers
0
68
136
205
273
341
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000328
AC:
50
AN:
152308
Hom.:
1
Cov.:
33
AF XY:
0.000510
AC XY:
38
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.0000241
AC:
0.0000240547
AN:
0.0000240547
Gnomad4 AMR
AF:
0.000196
AC:
0.000196181
AN:
0.000196181
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.00911
AC:
0.0091135
AN:
0.0091135
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.0000294
AC:
0.0000293997
AN:
0.0000293997
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000140
Hom.:
0
Bravo
AF:
0.000238
ExAC
AF:
0.00166
AC:
201
Asia WGS
AF:
0.00462
AC:
16
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cataract 2, multiple types Uncertain:2Benign:1
May 28, 2019
Mendelics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:research

The heterozygous p.Arg168Trp variant in CRYGC has been identified in 2 relatives from 1 family with cataracts (PMID: 12011157), but has also been identified in >1% of chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant cataracts. -

Jul 26, 2007
OMIM
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Nuclear pulverulent cataract Uncertain:1
Jan 11, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 168 of the CRYGC protein (p.Arg168Trp). This variant is present in population databases (rs28931604, gnomAD 1.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with congenital cataracts (PMID: 17679936, 18587492). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16945). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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
Uncertain
0.41
BayesDel_addAF
Benign
-0.057
T
BayesDel_noAF
Pathogenic
0.16
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D
Eigen
Benign
0.12
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.27
N
MetaRNN
Benign
0.023
T
MetaSVM
Uncertain
0.77
D
MutationAssessor
Pathogenic
4.4
H
PrimateAI
Benign
0.36
T
PROVEAN
Pathogenic
-7.1
D
REVEL
Pathogenic
0.68
Sift
Uncertain
0.0080
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.96
D
Vest4
0.60
MVP
0.90
MPC
0.40
ClinPred
0.24
T
GERP RS
-0.34
Varity_R
0.52
gMVP
0.72
Mutation Taster
=85/15
polymorphism

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

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

Other links and lift over

dbSNP: rs28931604; hg19: chr2-208992950; COSMIC: COSV52204992; COSMIC: COSV52204992; API