NM_000180.4:c.238_252delGCCGCCGCCCGCCTG

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM4PP3PP5

The NM_000180.4(GUCY2D):c.238_252delGCCGCCGCCCGCCTG(p.Ala80_Leu84del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000734 in 1,498,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000059 ( 0 hom. )

Consequence

GUCY2D
NM_000180.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 8.88

Variant links:

Genes affected

GUCY2D (HGNC:4689): (guanylate cyclase 2D, retinal) This gene encodes a retina-specific guanylate cyclase, which is a member of the membrane guanylyl cyclase family. Like other membrane guanylyl cyclases, this enzyme has a hydrophobic amino-terminal signal sequence followed by a large extracellular domain, a single membrane spanning domain, a kinase homology domain, and a guanylyl cyclase catalytic domain. In contrast to other membrane guanylyl cyclases, this enzyme is not activated by natriuretic peptides. Mutations in this gene result in Leber congenital amaurosis and cone-rod dystrophy-6 diseases. [provided by RefSeq, Dec 2008]

GUCY2D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000180.4.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 17-8003272-GGCCGCCCGCCTGGCC-G is Pathogenic according to our data. Variant chr17-8003272-GGCCGCCCGCCTGGCC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437979.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}. Variant chr17-8003272-GGCCGCCCGCCTGGCC-G is described in Lovd as [Pathogenic]. Variant chr17-8003272-GGCCGCCCGCCTGGCC-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2D	NM_000180.4 link	c.238_252delGCCGCCGCCCGCCTG	p.Ala80_Leu84del	conservative_inframe_deletion	Exon 2 of 20	ENST00000254854.5	NP_000171.1	Q02846
GUCY2D	XM_011523816.2 link	c.238_252delGCCGCCGCCCGCCTG	p.Ala80_Leu84del	conservative_inframe_deletion	Exon 1 of 19		XP_011522118.1	Q02846

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5 link	c.238_252delGCCGCCGCCCGCCTG	p.Ala80_Leu84del	conservative_inframe_deletion	Exon 2 of 20	1	NM_000180.4	ENSP00000254854.4		Q02846

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000213

AC:

AN:

93704

Hom.:

AF XY:

0.0000189

AC XY:

AN XY:

52908

show subpopulations

Gnomad AFR exome

AF:

0.000832

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000554

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000594

AC:

AN:

1346668

Hom.:

AF XY:

0.00000753

AC XY:

AN XY:

663880

show subpopulations

Gnomad4 AFR exome

AF:

0.000111

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000134

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000283

Gnomad4 OTH exome

AF:

0.0000179

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Jan 22, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone dystrophy

Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified

Uncertain:1

Jan 08, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GUCY2D c.238_252del15 (p.Ala80_Leu84del) results in an in-frame deletion that is predicted to remove five amino acids from the encoded protein. The variant allele was found at a frequency of 2.1e-05 in 93704 control chromosomes. c.238_252del15 has been reported in the literature in setting of WGS or WES in compound heterozygous individuals affected with cone/cone-rod dystrophy (e.g. Carss_2017, Liu_2020) or in at least one individual affected with an autosomal recessive inherited retinal disease without reported genotype (e.g. Karali_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28041643, 36460718, 32821499). ClinVar contains an entry for this variant (Variation ID: 437979). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1

Uncertain:1

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.238_252del, results in the deletion of 5 amino acid(s) of the GUCY2D protein (p.Ala80_Leu84del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.09%). This variant has been observed in individual(s) with cone-rod dystrophy, inherited retinal disease, and/or Leber congenital amaurosis (PMID: 28041643, 32581362, 32821499, 36460718). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 437979). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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