2-208128311-GTAGTTG-TCTACGAGGGTATTGCCCCGTCTACGAGGTATTGCCCGTCTACGAGGGTATTGCCCCGTCTACGA

Position:

• chr2-208128311-GTAGTTG-TCTACGAGGGTATTGCCCCGTCTACGAGGTATTGCCCGTCTACGAGGGTATTGCCCCGTCTACGA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_020989.4(CRYGC):​c.411_417delinsTCGTAGACGGGGCAATACCCTCGTAGACGGGCAATACCTCGTAGACGGGGCAATACCCTCGTAGA​(p.Asn138ArgfsTer21) variant causes a stop gained, frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRYGC NM_020989.4 stop_gained, frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.18

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]

LOC100507443 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-208128311-GTAGTTG-TCTACGAGGGTATTGCCCCGTCTACGAGGTATTGCCCGTCTACGAGGGTATTGCCCCGTCTACGA is Pathogenic according to our data. Variant chr2-208128311-GTAGTTG-TCTACGAGGGTATTGCCCCGTCTACGAGGTATTGCCCGTCTACGAGGGTATTGCCCCGTCTACGA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2031157.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYGC	NM_020989.4	c.411_417delinsTCGTAGACGGGGCAATACCCTCGTAGACGGGCAATACCTCGTAGACGGGGCAATACCCTCGTAGA	p.Asn138ArgfsTer21	stop_gained, frameshift_variant	3/3	ENST00000282141.4	NP_066269.1
LOC100507443	NR_038437.1	n.98-8745_98-8739delinsTCTACGAGGGTATTGCCCCGTCTACGAGGTATTGCCCGTCTACGAGGGTATTGCCCCGTCTACGA		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYGC	ENST00000282141.4	c.411_417delinsTCGTAGACGGGGCAATACCCTCGTAGACGGGCAATACCTCGTAGACGGGGCAATACCCTCGTAGA	p.Asn138ArgfsTer21	stop_gained, frameshift_variant	3/3	1	NM_020989.4	ENSP00000282141	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nuclear pulverulent cataract Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This premature translational stop signal has been observed in individual(s) with congenital cataracts (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn138Argfs*21) in the CRYGC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the CRYGC protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-208993035;