rs9905402

Positions:

chr17-8003108-T-C

Variant summary

Our verdict is Benign. Variant got -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

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/exons	MANE	Protein	UniProt
GUCY2D	NM_000180.4 link	c.61T>C	p.Trp21Arg	missense_variant	2/20	ENST00000254854.5	NP_000171.1	Q02846
GUCY2D	XM_011523816.2 link	c.61T>C	p.Trp21Arg	missense_variant	1/19		XP_011522118.1	Q02846

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5 link	c.61T>C	p.Trp21Arg	missense_variant	2/20	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

GnomAD3 exomes

AF:

0.0480

AC:

5516

AN:

114956

Hom.:

258

AF XY:

0.0504

AC XY:

3202

AN XY:

63542

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 SAS exome

AF:

0.104

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

Gnomad4 AFR exome

AF:

0.259

Gnomad4 AMR exome

AF:

0.0491

Gnomad4 ASJ exome

AF:

0.0509

Gnomad4 EAS exome

AF:

0.0109

Gnomad4 SAS exome

AF:

0.111

Gnomad4 FIN exome

AF:

0.0194

Gnomad4 NFE exome

AF:

0.0216

Gnomad4 OTH exome

AF:

0.0513

GnomAD4 genome

AF:

0.0964

AC:

14652

AN:

152058

Hom.:

1514

Cov.:

AF XY:

0.0957

AC XY:

7114

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.258

Gnomad4 AMR

AF:

0.0697

Gnomad4 ASJ

AF:

0.0625

Gnomad4 EAS

AF:

0.0307

Gnomad4 SAS

AF:

0.123

Gnomad4 FIN

AF:

0.0216

Gnomad4 NFE

AF:

0.0224

Gnomad4 OTH

AF:

0.0750

Alfa

AF:

0.0472

Hom.:

103

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2019	This variant is associated with the following publications: (PMID: 24066033, 27884173, 16123401, 20981092, 18055820, 15111605) -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2016	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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.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

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

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

Varity_R

0.048

gMVP

0.42

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