17-8014859-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BS2BA1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000180.4(GUCY2D):c.2577G>T (p.Pro859=) variant is located at the first base of exon 14 and does not alter the amino acid (proline) at position p.859. The splicing impact predictor SpliceAI gives a delta score of 0.03, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.04139, with 3871 alleles / 91074 total alleles in the South Asian population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.016 (BA1). This variant has been found in the homozygous state in 141 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, BP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA201118/MONDO:0100453/167

Frequency

Genomes: 𝑓 0.0059 ( 14 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 127 hom. )

Consequence

GUCY2D
NM_000180.4 splice_region, synonymous

Scores

Splicing: ADA: 0.7349

Clinical Significance

Benign reviewed by expert panel B:6

Conservation

PhyloP100: 0.332

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:

ENSG00000279174 (HGNC:):

ENSG00000279174 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2D	NM_000180.4 link	c.2577G>T	p.Pro859Pro	splice_region_variant, synonymous_variant	Exon 14 of 20	ENST00000254854.5	NP_000171.1	Q02846
GUCY2D	XM_011523816.2 link	c.2577G>T	p.Pro859Pro	splice_region_variant, synonymous_variant	Exon 13 of 19		XP_011522118.1	Q02846

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5 link	c.2577G>T	p.Pro859Pro	splice_region_variant, synonymous_variant	Exon 14 of 20	1	NM_000180.4	ENSP00000254854.4		Q02846
ENSG00000279174	ENST00000623126.1 link	n.1520C>A		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.00581

AC:

884

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0139

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0481

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00679

AC:

1707

AN:

251356

Hom.:

AF XY:

0.00834

AC XY:

1133

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0428

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000634

Gnomad OTH exome

AF:

0.00472

GnomAD4 exome

AF:

0.00360

AC:

5265

AN:

1461852

Hom.:

127

Cov.:

AF XY:

0.00470

AC XY:

3420

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0155

Gnomad4 AMR exome

AF:

0.00105

Gnomad4 ASJ exome

AF:

0.00295

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0422

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000587

Gnomad4 OTH exome

AF:

0.00517

GnomAD4 genome

AF:

0.00587

AC:

893

AN:

152250

Hom.:

Cov.:

AF XY:

0.00629

AC XY:

468

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0140

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0485

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00140

Hom.:

Bravo

AF:

0.00516

Asia WGS

AF:

0.0310

AC:

109

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 13, 2015	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2025

- -

GUCY2D-related recessive retinopathy

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen

Jan 30, 2025

The NM_000180.4(GUCY2D):c.2577G>T (p.Pro859=) variant is located at the first base of exon 14 and does not alter the amino acid (proline) at position p.859. The splicing impact predictor SpliceAI gives a delta score of 0.03, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.04139, with 3871 alleles / 91074 total alleles in the South Asian population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.016 (BA1). This variant has been found in the homozygous state in 141 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, BP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.73

dbscSNV1_RF

Pathogenic

0.82

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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