2-208124294-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PM2PM5PP5_Very_StrongBP4

The NM_006891.4(CRYGD):c.70C>A(p.Pro24Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P24S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CRYGD
NM_006891.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: -2.14

Publications

38 publications found

Variant links:

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 types
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
cataract - microcornea syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cerulean cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
coralliform cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset lamellar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pulverulent cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CRYGD links:

ENSG00000295187 (HGNC:):

ENSG00000295187 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-208124294-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16942.Status of the report is no_assertion_criteria_provided, 0 stars.

PP5

Variant 2-208124294-G-T is Pathogenic according to our data. Variant chr2-208124294-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.3742622). . Strength limited to SUPPORTING due to the PP5.

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.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYGD	NM_006891.4	MANE Select	c.70C>A	p.Pro24Thr	missense	Exon 2 of 3	NP_008822.2
	LOC100507443	NR_038437.1		n.97+5069G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CRYGD	ENST00000264376.5	TSL:1 MANE Select	c.70C>A	p.Pro24Thr	missense	Exon 2 of 3	ENSP00000264376.4
ENSG00000295187	ENST00000728538.1		n.100+5069G>T		intron	N/A
ENSG00000295187	ENST00000728539.1		n.117+5069G>T		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000418

AC:

AN:

239490

AF XY:

0.00000767

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000137

AC:

AN:

1458632

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725410

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26014

East Asian (EAS)

AF:

0.00

AC:

AN:

39600

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110890

Other (OTH)

AF:

0.00

AC:

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 4 multiple types

Pathogenic:2

Jan 01, 2023

Molecular Medicine, University of Pavia

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Sep 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

CRYGD-related disorder

Pathogenic:1

Jul 12, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CRYGD c.70C>A variant is predicted to result in the amino acid substitution p.Pro24Thr. This variant, also described in the literature as P23T, has been reported in the heterozygous state in many individuals and families with cataracts (Family C87, Santhiya et al. 2002. PubMed ID: 12011157; Fan et al. 2020. PubMed ID: 32883240; Family A, Vanita. 2012. PubMed ID: 22669729; Liu et al. 2023. PubMed ID: 37337769). Functional studies have shown that this variants leads to lowered solubility of the protein, making it prone to aggregation (Banerjee et al. 2012. PubMed ID: 21827768; Boatz et al. 2017. PubMed ID: 28474685; Pande et al. 2010. PubMed ID: 20553008). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. Of note, another variant impacting the same amino acid residue (p.Pro24Ser) has also been reported to segregate in a large family with cataracts (referred to as P23S, Plotnikova et al. 2007. PubMed ID: 17564961). Based on this evidence, we interpret the c.70C>A (p.Pro24Thr) variant as pathogenic.

not provided

Pathogenic:1

Oct 04, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies suggest this variant (described as P23T) causes misfolding and protein aggregation (PMID: 22520268); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19275895, 23141511, 25403472, 26694549, 29914532, 29652984, 19218553, 12011157, 19216553, 20553008, 21827768, 23670788, 28474685, 23936409, 15709761, 22669729, 32148946, 32830442, 12676897, 28450710, 33510601, 31523120, 34150533, 14767902, 19668596, 35222542, 26732753, 37480084, 34169787, 38840272, 32883240, 34671977, 37337769, 36729443, 22520268)

Aculeiform cataract

Pathogenic:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 24 of the CRYGD protein (p.Pro24Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with congenital cataracts (PMID: 25403472, 26694549). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Pro23Thr. ClinVar contains an entry for this variant (Variation ID: 16940). 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 tolerated. Experimental studies have shown that this missense change affects CRYGD function (PMID: 21827768, 28474685). For these reasons, this variant has been classified as Pathogenic.

Developmental cataract

Pathogenic:1

Jan 09, 2015

Eye Genetics Research Group, Children's Medical Research Institute

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.010

BayesDel_noAF

Benign

-0.15

CADD

Benign

0.27

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.27

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.096

M_CAP

Benign

0.051

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.9

PhyloP100

-2.1

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.51

Sift

Benign

0.064

Sift4G

Benign

0.10

Polyphen

0.084

Vest4

0.12

MutPred

0.84

Gain of catalytic residue at P24 (P = 0.0857)

MVP

0.59

MPC

0.49

ClinPred

0.35

GERP RS

-6.5

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.26

gMVP

0.71

Mutation Taster

=45/55

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over