rs202233735

chr2-208124196-G-Cchr2-208124196-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PVS1_Strong BP6 BS1 BS2

The NM_006891.4(CRYGD):c.168C>G(p.Tyr56Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,611,514 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (33 hom.)
• Consequence: CRYGD NM_006891.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 2.27

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]

LOC100507443 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 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 18 pathogenic variants in the truncated region.
• BP6: Variant 2-208124196-G-C is Benign according to our data. Variant chr2-208124196-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 333874.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=3, Uncertain_significance=1}. Variant chr2-208124196-G-C is described in Lovd as [Pathogenic]. Variant chr2-208124196-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00401 (611/152234) while in subpopulation AMR AF= 0.0165 (252/15300). AF 95% confidence interval is 0.0148. There are 5 homozygotes in gnomad4. There are 301 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 604 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYGD	NM_006891.4	c.168C>G	p.Tyr56Ter	stop_gained	2/3	ENST00000264376.5
LOC100507443	NR_038437.1	n.97+4971G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYGD	ENST00000264376.5	c.168C>G	p.Tyr56Ter	stop_gained	2/3	1	NM_006891.4	P1

Frequencies

GnomAD3 genomes AF: 0.00397 AC: 604 AN: 152116 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00340

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00627 AC: 1554 AN: 248012 Hom.: 19 AF XY: 0.00522 AC XY: 705 AN XY: 134952

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.0310

Gnomad ASJ exome AF: 0.00441

Gnomad EAS exome AF: 0.00273

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.000326

Gnomad NFE exome AF: 0.00268

Gnomad OTH exome AF: 0.00445

GnomAD4 exome AF: 0.00376 AC: 5480 AN: 1459280 Hom.: 33 Cov.: 30 AF XY: 0.00355 AC XY: 2577 AN XY: 725950

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.0301

Gnomad4 ASJ exome AF: 0.00490

Gnomad4 EAS exome AF: 0.00186

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.000379

Gnomad4 NFE exome AF: 0.00316

Gnomad4 OTH exome AF: 0.00345

GnomAD4 genome AF: 0.00401 AC: 611 AN: 152234 Hom.: 5 Cov.: 33 AF XY: 0.00404 AC XY: 301 AN XY: 74420

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.0165

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00340

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00275 Hom.: 1

Bravo AF: 0.00585

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00311 AC: 12

ExAC AF: 0.00507 AC: 615

EpiCase AF: 0.00344

EpiControl AF: 0.00255

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cataract 4 multiple types Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 31, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2020	This variant is associated with the following publications: (PMID: 31216405, 28849415, 27959697, 27535533, 19390652, 22995991) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	CRYGD: BS1, BS2 -

Joubert syndrome 17 Benign:1

Likely benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous p.Tyr56Ter variant in CRYGD has been identified in 3 Brazilian relatives from 1 family with cataracts (PMID: 19390652), but has also been identified in >3% of Latino chromosomes and 4 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. -

CRYGD-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Aculeiform cataract Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	37
Dann	Uncertain	0.99
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A
Vest4		0.67
GERP RS		3.4

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

Other links and lift over

dbSNP: rs202233735; hg19: chr2-208988920;