Variant chr17-8003049-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_000180.4(GUCY2D):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,373,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

GUCY2D
NM_000180.4 start_lost

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.09

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_000180.4 (GUCY2D) was described as [Likely_pathogenic] in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-8003049-T-C is Pathogenic according to our data. Variant chr17-8003049-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3381797.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCY2D	NM_000180.4 link	c.2T>C	p.Met1?	start_lost	2/20	ENST00000254854.5	NP_000171.1	Q02846
GUCY2D	XM_011523816.2 link	c.2T>C	p.Met1?	start_lost	1/19		XP_011522118.1	Q02846

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5 link	c.2T>C	p.Met1?	start_lost	2/20	1	NM_000180.4	ENSP00000254854.4		Q02846

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1373878

Hom.:

Cov.:

AF XY:

0.00000295

AC XY:

AN XY:

677916

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000258

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Retinal dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

May 27, 2024

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.085

Eigen

Benign

-0.056

Eigen_PC

Benign

-0.011

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.98

MetaSVM

Benign

-0.37

PROVEAN

Benign

-0.33

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.42

Vest4

0.62

MutPred

0.99

Gain of glycosylation at M1 (P = 0.0342);

MVP

0.88

ClinPred

0.99

GERP RS

3.3

Varity_R

0.86

gMVP

0.68

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over