rs8069344

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.2345T>A (p.Leu782His) variant is predicted to change the leucine at position p.782 to histidine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.3995, with 30227 alleles / 74954 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 17920 adult individuals in gnomAD (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.119, 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, 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/CA8366093/MONDO:0100453/167

Frequency

Genomes: 𝑓 0.19 ( 4051 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13869 hom. )

Consequence

GUCY2D
NM_000180.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:10

Conservation

PhyloP100: 2.36

Publications

29 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:

ENSG00000279174 (HGNC:):

ENSG00000279174 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.2345T>A	p.Leu782His	missense_variant	Exon 12 of 20	ENST00000254854.5	NP_000171.1	Q02846
GUCY2D	XM_011523816.2 link	c.2345T>A	p.Leu782His	missense_variant	Exon 11 of 19		XP_011522118.1	Q02846

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5 link	c.2345T>A	p.Leu782His	missense_variant	Exon 12 of 20	1	NM_000180.4	ENSP00000254854.4		Q02846
ENSG00000279174	ENST00000623126.1 link	n.2418A>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.192

AC:

29181

AN:

152088

Hom.:

4029

Cov.:

show subpopulations

Gnomad AFR

AF:

0.399

Gnomad AMI

AF:

0.0757

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.152

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.114

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.167

GnomAD2 exomes

AF:

0.123

AC:

30853

AN:

251294

AF XY:

0.120

show subpopulations

Gnomad AFR exome

AF:

0.404

Gnomad AMR exome

AF:

0.0602

Gnomad ASJ exome

AF:

0.150

Gnomad EAS exome

AF:

0.000707

Gnomad FIN exome

AF:

0.121

Gnomad NFE exome

AF:

0.121

Gnomad OTH exome

AF:

0.118

GnomAD4 exome

AF:

0.127

AC:

185391

AN:

1461062

Hom.:

13869

Cov.:

AF XY:

0.126

AC XY:

91788

AN XY:

726852

show subpopulations

African (AFR)

AF:

0.408

AC:

13652

AN:

33448

American (AMR)

AF:

0.0646

AC:

2888

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.149

AC:

3891

AN:

26132

East Asian (EAS)

AF:

0.000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.116

AC:

9988

AN:

86250

European-Finnish (FIN)

AF:

0.121

AC:

6455

AN:

53256

Middle Eastern (MID)

AF:

0.137

AC:

790

AN:

5768

European-Non Finnish (NFE)

AF:

0.126

AC:

139636

AN:

1111416

Other (OTH)

AF:

0.134

AC:

8071

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

8432

16863

25295

33726

42158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5130

10260

15390

20520

25650

<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:

0.192

AC:

29245

AN:

152206

Hom.:

4051

Cov.:

AF XY:

0.188

AC XY:

13972

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.399

AC:

16575

AN:

41506

American (AMR)

AF:

0.104

AC:

1588

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.152

AC:

529

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5184

South Asian (SAS)

AF:

0.118

AC:

571

AN:

4824

European-Finnish (FIN)

AF:

0.114

AC:

1206

AN:

10610

Middle Eastern (MID)

AF:

0.167

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.122

AC:

8305

AN:

68004

Other (OTH)

AF:

0.166

AC:

350

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1113

2225

3338

4450

5563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

286

572

858

1144

1430

<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:

0.131

Hom.:

1172

Bravo

AF:

0.199

TwinsUK

AF:

0.129

AC:

477

ALSPAC

AF:

0.129

AC:

498

ESP6500AA

AF:

0.395

AC:

1740

ESP6500EA

AF:

0.125

AC:

1078

ExAC

AF:

0.130

AC:

15796

Asia WGS

AF:

0.0870

AC:

306

AN:

3478

EpiCase

AF:

0.120

EpiControl

AF:

0.117

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 03, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 11035546, 17964524, 18161624, 29178642, 17344846, 20079931, 16741161) -

Cone-rod dystrophy 6

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Night blindness, congenital stationary, type1i

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leber congenital amaurosis 1

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Choroidal dystrophy, central areolar, 1

Benign:1

Aug 10, 2021

Genome-Nilou Lab

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.2345T>A (p.Leu782His) variant is predicted to change the leucine at position p.782 to histidine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.3995, with 30227 alleles / 74954 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 17920 adult individuals in gnomAD (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.119, 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, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.15

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.057

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.020

PhyloP100

2.4

PrimateAI

Benign

0.31

PROVEAN

Benign

2.0

REVEL

Benign

0.12

Sift

Benign

0.11

Sift4G

Uncertain

0.058

Polyphen

0.0

Vest4

0.052

MPC

0.28

ClinPred

0.0075

GERP RS

3.1

Varity_R

0.087

gMVP

0.52

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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