chr2-208124294-G-T

Position:

chr2-208124294-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PM5PP5_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. 15/21 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

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 links:

LOC100507443 (HGNC:):

LOC100507443 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a mutagenesis_site Slightly reduces solubility. (size 0) in uniprot entity CRGD_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_006891.4

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 Lovd as [Pathogenic].

PP5

Variant 2-208124294-G-T is Pathogenic according to our data. Variant chr2-208124294-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208124294-G-T is described in Lovd as [Likely_pathogenic]. Variant chr2-208124294-G-T is described in Lovd as [Pathogenic]. Variant chr2-208124294-G-T is described in Lovd as [Pathogenic]. Variant chr2-208124294-G-T is described in Lovd as [Likely_pathogenic].

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYGD	NM_006891.4 linkuse as main transcript	c.70C>A	p.Pro24Thr	missense_variant	2/3	ENST00000264376.5	NP_008822.2	P07320A0A140CTX7
LOC100507443	NR_038437.1 linkuse as main transcript	n.97+5069G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYGD	ENST00000264376.5 linkuse as main transcript	c.70C>A	p.Pro24Thr	missense_variant	2/3	1	NM_006891.4	ENSP00000264376.4		P07320

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000418

AC:

AN:

239490

Hom.:

AF XY:

0.00000767

AC XY:

AN XY:

130462

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:

0.0000334

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

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2007	- -
Likely pathogenic, criteria provided, single submitter	research	Molecular Medicine, University of Pavia	Jan 01, 2023	- -

CRYGD-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2024

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

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 22, 2023

Published functional studies suggest this variant (described as P23T) causes misfolding and protein aggregation (Moreau et al., 2012); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19275895, 32883240, 34169787, 23141511, 25403472, 26694549, 26732753, 29914532, 29652984, 19218553, 12011157, 19216553, 20553008, 21827768, 23670788, 28474685, 23936409, 15709761, 22669729, 22520268, 32148946, 32830442, 12676897, 28450710, 33510601, 31523120, 34150533, 14767902, 19668596, 35222542) -

Aculeiform cataract

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 11, 2023

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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CRYGD function (PMID: 21827768, 28474685). 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. ClinVar contains an entry for this variant (Variation ID: 16940). This variant is also known as p.Pro23Thr. 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. -

Developmental cataract

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Eye Genetics Research Group, Children's Medical Research Institute

Jan 09, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.010

BayesDel_noAF

Benign

-0.15

CADD

Benign

0.27

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

MutationTaster

Benign

0.92

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

Varity_R

0.26

gMVP

0.71

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over