chr17-8003108-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS2BP4BA1

This summary comes from the ClinGen Evidence Repository: The NM_000180.4(GUCY2D):c.61T>C (p.Trp21Arg) variant is a missense variant predicted to replace the tryptophan at position p.21 with arginine. This variant is present in gnomAD v4.1.0 at a GrpMax allele frequency of 0.2550, with 18,276 alleles / 70,794 total alleles in the African/African American 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 3,593 adult individuals in gnomAD v4.1.0, which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.141, 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 0.01 for acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). The variant exhibited ~100% enzymatic activity in a guanylate cyclase assay relative to the wild-type control, which is higher than the ClinGen LCA/eoRD VCEP BS3_Supporting threshold of >50% activity, indicating that it does not trigger a severe defect in protein function, however, it lies in the signal peptide and may be considered ineligible for PS3 or BS3 due to incompatibility with in vitro activity assays (PMID:11328726, Figure 1). 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, and BP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA145844/MONDO:0100453/167

Frequency

Genomes: 𝑓 0.096 ( 1514 hom., cov: 33)

Exomes 𝑓: 0.034 ( 2079 hom. )

Consequence

GUCY2D
NM_000180.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:8O:1

Conservation

PhyloP100: 0.241

Publications

16 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.61T>C	p.Trp21Arg	missense_variant	Exon 2 of 20	ENST00000254854.5	NP_000171.1	Q02846
GUCY2D	XM_011523816.2 link	c.61T>C	p.Trp21Arg	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.61T>C	p.Trp21Arg	missense_variant	Exon 2 of 20	1	NM_000180.4	ENSP00000254854.4		Q02846

Frequencies

GnomAD3 genomes

AF:

0.0961

AC:

14595

AN:

151950

Hom.:

1500

Cov.:

show subpopulations

Gnomad AFR

AF:

0.257

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.0697

Gnomad ASJ

AF:

0.0625

Gnomad EAS

AF:

0.0310

Gnomad SAS

AF:

0.122

Gnomad FIN

AF:

0.0216

Gnomad MID

AF:

0.0605

Gnomad NFE

AF:

0.0224

Gnomad OTH

AF:

0.0748

GnomAD2 exomes

AF:

0.0480

AC:

5516

AN:

114956

AF XY:

0.0504

show subpopulations

Gnomad AFR exome

AF:

0.202

Gnomad AMR exome

AF:

0.0449

Gnomad ASJ exome

AF:

0.0482

Gnomad EAS exome

AF:

0.0225

Gnomad FIN exome

AF:

0.0207

Gnomad NFE exome

AF:

0.0216

Gnomad OTH exome

AF:

0.0405

GnomAD4 exome

AF:

0.0340

AC:

46528

AN:

1369480

Hom.:

2079

Cov.:

AF XY:

0.0355

AC XY:

23977

AN XY:

675380

show subpopulations

African (AFR)

AF:

0.259

AC:

7588

AN:

29326

American (AMR)

AF:

0.0491

AC:

1696

AN:

34558

Ashkenazi Jewish (ASJ)

AF:

0.0509

AC:

1254

AN:

24614

East Asian (EAS)

AF:

0.0109

AC:

375

AN:

34382

South Asian (SAS)

AF:

0.111

AC:

8579

AN:

76986

European-Finnish (FIN)

AF:

0.0194

AC:

665

AN:

34258

Middle Eastern (MID)

AF:

0.0474

AC:

234

AN:

4934

European-Non Finnish (NFE)

AF:

0.0216

AC:

23199

AN:

1073200

Other (OTH)

AF:

0.0513

AC:

2938

AN:

57222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

2173

4346

6520

8693

10866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1068

2136

3204

4272

5340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0964

AC:

14652

AN:

152058

Hom.:

1514

Cov.:

AF XY:

0.0957

AC XY:

7114

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.258

AC:

10688

AN:

41468

American (AMR)

AF:

0.0697

AC:

1066

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0625

AC:

217

AN:

3472

East Asian (EAS)

AF:

0.0307

AC:

158

AN:

5144

South Asian (SAS)

AF:

0.123

AC:

591

AN:

4816

European-Finnish (FIN)

AF:

0.0216

AC:

229

AN:

10606

Middle Eastern (MID)

AF:

0.0616

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0224

AC:

1525

AN:

67948

Other (OTH)

AF:

0.0750

AC:

158

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

606

1212

1817

2423

3029

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

304

456

608

760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0525

Hom.:

211

Bravo

AF:

0.102

ESP6500AA

AF:

0.117

AC:

278

ESP6500EA

AF:

0.0120

AC:

ExAC

AF:

0.0261

AC:

1225

Asia WGS

AF:

0.110

AC:

384

AN:

3466

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 03, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24066033, 27884173, 16123401, 20981092, 18055820, 15111605) -

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Jun 23, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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.61T>C (p.Trp21Arg) variant is a missense variant predicted to replace the tryptophan at position p.21 with arginine. This variant is present in gnomAD v4.1.0 at a GrpMax allele frequency of 0.2550, with 18,276 alleles / 70,794 total alleles in the African/African American 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 3,593 adult individuals in gnomAD v4.1.0, which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.141, 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 0.01 for acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). The variant exhibited ~100% enzymatic activity in a guanylate cyclase assay relative to the wild-type control, which is higher than the ClinGen LCA/eoRD VCEP BS3_Supporting threshold of >50% activity, indicating that it does not trigger a severe defect in protein function, however, it lies in the signal peptide and may be considered ineligible for PS3 or BS3 due to incompatibility with in vitro activity assays (PMID: 11328726, Figure 1). 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, and BP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.56

CADD

Benign

3.3

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.11

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.00032

LIST_S2

Benign

0.12

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.2

PhyloP100

0.24

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.0

REVEL

Benign

0.14

Sift

Benign

0.90

Sift4G

Benign

0.72

Polyphen

0.0

Vest4

0.041

MutPred

0.64

Gain of methylation at W21 (P = 0.0095);

MPC

2.1

ClinPred

0.000022

GERP RS

0.63

PromoterAI

0.030

Neutral

(source)

Varity_R

0.048

gMVP

0.42

Mutation Taster

=99/1

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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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