2-208128448-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The ENST00000282141.4(CRYGC):ā€‹c.280G>Cā€‹(p.Glu94Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. E94K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

CRYGC
ENST00000282141.4 missense

Scores

3
9
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.15
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 made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-208128448-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CRYGCNM_020989.4 linkuse as main transcriptc.280G>C p.Glu94Gln missense_variant 3/3 ENST00000282141.4 NP_066269.1
LOC100507443NR_038437.1 linkuse as main transcriptn.98-8608C>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CRYGCENST00000282141.4 linkuse as main transcriptc.280G>C p.Glu94Gln missense_variant 3/31 NM_020989.4 ENSP00000282141 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251026
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135718
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461882
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
0.0083
T
BayesDel_noAF
Benign
-0.23
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.97
D
M_CAP
Benign
0.068
D
MetaRNN
Pathogenic
0.93
D
MetaSVM
Uncertain
0.71
D
MutationAssessor
Pathogenic
3.5
H
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.48
T
PROVEAN
Uncertain
-2.8
D
REVEL
Uncertain
0.55
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.028
D
Polyphen
0.98
D
Vest4
0.51
MutPred
0.87
Gain of MoRF binding (P = 0.057);
MVP
0.91
MPC
0.32
ClinPred
0.99
D
GERP RS
5.3
Varity_R
0.59
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs200572745; hg19: chr2-208993172; API