chr2-208128258-C-T

Variant names:

• chr2-208128258-C-T
• rs398122392
• NM_020989.4:c.470G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 PM2 PP5_Very_Strong

The NM_020989.4(CRYGC):​c.470G>A​(p.Trp157*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000890328: Functional studies with transfected W157X cells demonstrate self-aggregation and reduction in solubility that would be expected to generate light-scattering particles, compromising the transparency of the cells and their assemblies (Talla et. al, 2008)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRYGC NM_020989.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.52
• Publications: 3 publications found

Genes affected

CRYGC (HGNC:2410): (crystallin gamma C) This gene encodes a member of the beta/gamma-crystallin family of proteins. Crystallins constitute the major proteins of vertebrate eye lens and maintain the transparency and refractive index of the lens. This gene and several family members are present in a gene cluster on chromosome 2. Mutations in this gene have been shown to cause multiple types of cataract, including Coppock-like cataract and zonular pulverulent cataract, among others. [provided by RefSeq, Jan 2015]

CRYGC Gene-Disease associations (from GenCC):

• cataract 2, multiple types

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

  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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000890328: Functional studies with transfected W157X cells demonstrate self-aggregation and reduction in solubility that would be expected to generate light-scattering particles, compromising the transparency of the cells and their assemblies (Talla et. al, 2008).; SCV005562306: "In an assay testing CRYGC function, this variant showed a functionally abnormal result" (Talla, 2008).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-208128258-C-T is Pathogenic according to our data. Variant chr2-208128258-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 66074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020989.4. 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
	CRYGC	NM_020989.4	MANE Select	c.470G>A	p.Trp157*	stop_gained	Exon 3 of 3	NP_066269.1	P07315
	LOC100507443	NR_038437.1		n.98-8798C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYGC	ENST00000282141.4	TSL:1 MANE Select	c.470G>A	p.Trp157*	stop_gained	Exon 3 of 3	ENSP00000282141.3	P07315
	ENSG00000295187	ENST00000728538.1		n.101-8798C>T		intron	N/A
	ENSG00000295187	ENST00000728539.1		n.118-8798C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Cataract 2, multiple types (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		2.5
Vest4		0.71
GERP RS		5.0
Mutation Taster		=17/183	disease causing (ClinVar)

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: rs398122392; hg19: chr2-208992982;