rs61749665

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS2BA1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000180.4(GUCY2D):c.154G>T (p.Ala52Ser) variant is predicted to replace the alanine at position p.52 with serine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.6857, with 26306 alleles / 37974 total 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 95,479 adult individuals in gnomAD v4.1.0 (BS2). The computational predictor REVEL gives a score of 0.126, which is below the ClinGen LCA / eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.0, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). 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_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA145842/MONDO:0100453/167

Frequency

Genomes: 𝑓 0.31 ( 8439 hom., cov: 33)

Exomes 𝑓: 0.34 ( 87040 hom. )

Consequence

GUCY2D
NM_000180.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1B:15O:1

Conservation

PhyloP100: -0.508

Publications

24 publications found

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 Gene-Disease associations (from GenCC):

cone-rod dystrophy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
GUCY2D-related dominant retinopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
GUCY2D-related recessive retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Leber congenital amaurosis 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
cone-rod dystrophy 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
night blindness, congenital stationary, type1i
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
central areolar choroidal dystrophy
Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet

GUCY2D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.154G>T	p.Ala52Ser	missense_variant	Exon 2 of 20	ENST00000254854.5	NP_000171.1	Q02846
GUCY2D	XM_011523816.2 link	c.154G>T	p.Ala52Ser	missense_variant	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.154G>T	p.Ala52Ser	missense_variant	Exon 2 of 20	1	NM_000180.4	ENSP00000254854.4		Q02846

Frequencies

GnomAD3 genomes

AF:

0.311

AC:

47231

AN:

151842

Hom.:

8437

Cov.:

show subpopulations

Gnomad AFR

AF:

0.166

Gnomad AMI

AF:

0.341

Gnomad AMR

AF:

0.384

Gnomad ASJ

AF:

0.337

Gnomad EAS

AF:

0.679

Gnomad SAS

AF:

0.584

Gnomad FIN

AF:

0.411

Gnomad MID

AF:

0.341

Gnomad NFE

AF:

0.319

Gnomad OTH

AF:

0.312

GnomAD2 exomes

AF:

0.416

AC:

46515

AN:

111840

AF XY:

0.426

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.434

Gnomad ASJ exome

AF:

0.332

Gnomad EAS exome

AF:

0.695

Gnomad FIN exome

AF:

0.402

Gnomad NFE exome

AF:

0.312

Gnomad OTH exome

AF:

0.356

GnomAD4 exome

AF:

0.345

AC:

470659

AN:

1365212

Hom.:

87040

Cov.:

AF XY:

0.351

AC XY:

236627

AN XY:

673498

show subpopulations

African (AFR)

AF:

0.158

AC:

4415

AN:

28014

American (AMR)

AF:

0.429

AC:

14459

AN:

33690

Ashkenazi Jewish (ASJ)

AF:

0.328

AC:

7952

AN:

24230

East Asian (EAS)

AF:

0.695

AC:

22838

AN:

32864

South Asian (SAS)

AF:

0.579

AC:

44239

AN:

76354

European-Finnish (FIN)

AF:

0.404

AC:

15500

AN:

38390

Middle Eastern (MID)

AF:

0.324

AC:

1452

AN:

4476

European-Non Finnish (NFE)

AF:

0.317

AC:

339518

AN:

1070330

Other (OTH)

AF:

0.357

AC:

20286

AN:

56864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

15412

30825

46237

61650

77062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.311

AC:

47235

AN:

151950

Hom.:

8439

Cov.:

AF XY:

0.323

AC XY:

24004

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.166

AC:

6875

AN:

41508

American (AMR)

AF:

0.384

AC:

5865

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.337

AC:

1167

AN:

3468

East Asian (EAS)

AF:

0.679

AC:

3468

AN:

5110

South Asian (SAS)

AF:

0.582

AC:

2808

AN:

4822

European-Finnish (FIN)

AF:

0.411

AC:

4347

AN:

10564

Middle Eastern (MID)

AF:

0.318

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.319

AC:

21633

AN:

67892

Other (OTH)

AF:

0.317

AC:

670

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1607

3215

4822

6430

8037

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.313

Hom.:

2204

Bravo

AF:

0.297

TwinsUK

AF:

0.318

AC:

1179

ALSPAC

AF:

0.328

AC:

1264

ESP6500AA

AF:

0.126

AC:

396

ESP6500EA

AF:

0.243

AC:

1601

ExAC

AF:

0.295

AC:

22211

Asia WGS

AF:

0.596

AC:

2061

AN:

3466

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:15Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Mar 16, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4Other:1

Retina International

Significance:not provided

Review Status:no classification 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

- -

Department of Ophthalmology and Visual Sciences Kyoto University

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:2

Sep 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Leber congenital amaurosis 1

Pathogenic:1

Aug 01, 1998

OMIM

Significance:Pathogenic

Review Status:flagged submission

Collection Method:literature only

- -

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

The NM_000180.4(GUCY2D):c.154G>T (p.Ala52Ser) variant is predicted to replace the alanine at position p.52 with serine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.6857, with 26306 alleles / 37974 total 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 95,479 adult individuals in gnomAD v4.1.0 (BS2). The computational predictor REVEL gives a score of 0.126, which is below the ClinGen LCA / eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.0, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). 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_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). -

Cone-rod dystrophy 6

Benign:1

Oct 04, 2021

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Population allele frequency is 40% (rs61749665, 54,832/138,790 alleles in gnomAD v2.0.2). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria met: BA1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

2.0

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.12

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0000021

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.4

PhyloP100

-0.51

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.85

REVEL

Benign

0.13

Sift

Benign

0.20

Sift4G

Benign

0.28

Polyphen

0.17

Vest4

0.040

MPC

1.2

ClinPred

0.0024

GERP RS

0.19

Varity_R

0.052

gMVP

0.30

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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rs61749665

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over