rs34598902

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BS2BP4BA1

This summary comes from the ClinGen Evidence Repository: NM_000180.4(GUCY2D):c.2101C>T (p.Pro701Ser) is a missense variant that is predicted to replace proline at position p.701 with serine. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.2041, with 9318 / 44874 alleles in the East 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 2099 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of >6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.27, which is below the ClinGen LCA / eoRD VCEP threshold of <0.290 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). 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/CA200657/MONDO:0100453/167

Frequency

Genomes: 𝑓 0.039 ( 255 hom., cov: 32)

Exomes 𝑓: 0.033 ( 1844 hom. )

Consequence

GUCY2D
NM_000180.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:12O:1

Conservation

PhyloP100: 2.92

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 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.2101C>T	p.Pro701Ser	missense_variant	Exon 10 of 20	ENST00000254854.5	NP_000171.1	Q02846
GUCY2D	XM_011523816.2 link	c.2101C>T	p.Pro701Ser	missense_variant	Exon 9 of 19		XP_011522118.1	Q02846

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5 link	c.2101C>T	p.Pro701Ser	missense_variant	Exon 10 of 20	1	NM_000180.4	ENSP00000254854.4		Q02846

Frequencies

GnomAD3 genomes

AF:

0.0395

AC:

6004

AN:

152180

Hom.:

254

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0333

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0648

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.221

Gnomad SAS

AF:

0.0921

Gnomad FIN

AF:

0.0407

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0210

Gnomad OTH

AF:

0.0397

GnomAD3 exomes

AF:

0.0527

AC:

13104

AN:

248670

Hom.:

683

AF XY:

0.0526

AC XY:

7088

AN XY:

134724

show subpopulations

Gnomad AFR exome

AF:

0.0362

Gnomad AMR exome

AF:

0.0637

Gnomad ASJ exome

AF:

0.0238

Gnomad EAS exome

AF:

0.212

Gnomad SAS exome

AF:

0.0897

Gnomad FIN exome

AF:

0.0389

Gnomad NFE exome

AF:

0.0214

Gnomad OTH exome

AF:

0.0415

GnomAD4 exome

AF:

0.0332

AC:

48458

AN:

1460890

Hom.:

1844

Cov.:

AF XY:

0.0346

AC XY:

25146

AN XY:

726712

show subpopulations

Gnomad4 AFR exome

AF:

0.0350

Gnomad4 AMR exome

AF:

0.0624

Gnomad4 ASJ exome

AF:

0.0217

Gnomad4 EAS exome

AF:

0.206

Gnomad4 SAS exome

AF:

0.0907

Gnomad4 FIN exome

AF:

0.0368

Gnomad4 NFE exome

AF:

0.0207

Gnomad4 OTH exome

AF:

0.0448

GnomAD4 genome

AF:

0.0395

AC:

6012

AN:

152298

Hom.:

255

Cov.:

AF XY:

0.0434

AC XY:

3236

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0334

Gnomad4 AMR

AF:

0.0649

Gnomad4 ASJ

AF:

0.0222

Gnomad4 EAS

AF:

0.221

Gnomad4 SAS

AF:

0.0921

Gnomad4 FIN

AF:

0.0407

Gnomad4 NFE

AF:

0.0210

Gnomad4 OTH

AF:

0.0402

Alfa

AF:

0.0302

Hom.:

351

Bravo

AF:

0.0400

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0218

AC:

ESP6500AA

AF:

0.0388

AC:

171

ESP6500EA

AF:

0.0192

AC:

165

ExAC

AF:

0.0511

AC:

6200

Asia WGS

AF:

0.159

AC:

551

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

Department of Ophthalmology and Visual Sciences Kyoto University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27884173, 11035546, 23424971, 20981092, 18055820, 15111605) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:3

Oct 03, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 in 1000Genomes: 180/2178=8.2% -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis 1

Benign:1

Laboratory of Genetics in Ophthalmology, Institut Imagine

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GUCY2D-related recessive retinopathy

Benign:1

Jan 30, 2025

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

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

NM_000180.4(GUCY2D):c.2101C>T (p.Pro701Ser) is a missense variant that is predicted to replace proline at position p.701 with serine. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.2041, with 9318 / 44874 alleles in the East 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 2099 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of >6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.27, which is below the ClinGen LCA / eoRD VCEP threshold of <0.290 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). 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). -

Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1;C4551884:Choroidal dystrophy, central areolar, 1;C5231408:Night blindness, congenital stationary, type1i

Benign:1

Sep 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Benign:1

Jan 01, 2018

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.54

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0065

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.27

Sift

Benign

0.15

Sift4G

Benign

0.29

Polyphen

0.79

Vest4

0.15

MPC

0.68

ClinPred

0.030

GERP RS

4.4

Varity_R

0.088

gMVP

0.49

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

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