rs202233735

Variant names:

• chr2-208124196-G-C
• rs202233735
• NM_006891.4:c.168C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-208124196-G-C
• chr2-208124196-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1 BP6 BS1 BS2

The NM_006891.4(CRYGD):​c.168C>G​(p.Tyr56*) 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). Variant results in nonsense mediated mRNA decay.

• 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
• Publications: 20 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 types

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000295187 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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 VariationId is 333874.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 611 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYGD	NM_006891.4	MANE Select	c.168C>G	p.Tyr56*	stop_gained	Exon 2 of 3	NP_008822.2
	LOC100507443	NR_038437.1		n.97+4971G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYGD	ENST00000264376.5	TSL:1 MANE Select	c.168C>G	p.Tyr56*	stop_gained	Exon 2 of 3	ENSP00000264376.4	P07320
	ENSG00000295187	ENST00000728538.1		n.100+4971G>C		intron	N/A
	ENSG00000295187	ENST00000728539.1		n.117+4971G>C		intron	N/A

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

GnomAD2 exomes AF: 0.00627 AC: 1554 AN: 248012 AF XY: 0.00522

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00105 AC: 35 AN: 33400

American (AMR) AF: 0.0301 AC: 1345 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 128 AN: 26122

East Asian (EAS) AF: 0.00186 AC: 74 AN: 39688

South Asian (SAS) AF: 0.00154 AC: 133 AN: 86154

European-Finnish (FIN) AF: 0.000379 AC: 20 AN: 52818

Middle Eastern (MID) AF: 0.00412 AC: 19 AN: 4612

European-Non Finnish (NFE) AF: 0.00316 AC: 3518 AN: 1111602

Other (OTH) AF: 0.00345 AC: 208 AN: 60228

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00161 AC: 67 AN: 41508

American (AMR) AF: 0.0165 AC: 252 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00340 AC: 231 AN: 68016

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Cataract 4 multiple types (3)
-	-	2	not provided (2)
-	-	1	Aculeiform cataract (1)
-	-	1	CRYGD-related disorder (1)
-	-	1	Joubert syndrome 17 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.3
Vest4		0.67
GERP RS		3.4
PromoterAI		-0.098	Neutral
Mutation Taster		=39/161	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs202233735; hg19: chr2-208988920; COSMIC: COSV107266800; COSMIC: COSV107266800;