rs2242074
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PVS1_StrongPM2PP5_ModerateBS1_Supporting
The NM_006891.4(CRYGD):c.51T>G(p.Tyr17*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y17Y) has been classified as Benign.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
CRYGD
NM_006891.4 stop_gained
NM_006891.4 stop_gained
Scores
2
2
2
Clinical Significance
Conservation
PhyloP100: 0.446
Publications
1 publications found
Genes affected
CRYGD (HGNC:2411): (crystallin gamma D) 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]
CRYGD Gene-Disease associations (from GenCC):
- cataract 4 multiple typesInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- cataract - microcornea syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- cerulean cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- coralliform cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- early-onset lamellar cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- early-onset nuclear cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- pulverulent cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-208124313-A-C is Pathogenic according to our data. Variant chr2-208124313-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1300288.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000206 (3/1456780) while in subpopulation MID AF = 0.000348 (2/5744). AF 95% confidence interval is 0.0000611. There are 0 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 86. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_006891.4. You can select a different transcript below to see updated ACMG assignments.
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1456780Hom.: 0 Cov.: 86 AF XY: 0.00000414 AC XY: 3AN XY: 724314 show subpopulations
GnomAD4 exome
AF:
AC:
3
AN:
1456780
Hom.:
Cov.:
86
AF XY:
AC XY:
3
AN XY:
724314
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33432
American (AMR)
AF:
AC:
0
AN:
43870
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25982
East Asian (EAS)
AF:
AC:
0
AN:
39494
South Asian (SAS)
AF:
AC:
0
AN:
85754
European-Finnish (FIN)
AF:
AC:
0
AN:
52380
Middle Eastern (MID)
AF:
AC:
2
AN:
5744
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1109938
Other (OTH)
AF:
AC:
1
AN:
60186
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<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
GnomAD4 genome
Cov.:
33
ClinVar
ClinVar submissions
View on ClinVar Significance:Likely pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
PhyloP100
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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