rs34598902

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: 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

Publications

28 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000180.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2D	NM_000180.4	MANE Select	c.2101C>T	p.Pro701Ser	missense	Exon 10 of 20	NP_000171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2D	ENST00000254854.5	TSL:1 MANE Select	c.2101C>T	p.Pro701Ser	missense	Exon 10 of 20	ENSP00000254854.4

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

GnomAD2 exomes

AF:

0.0527

AC:

13104

AN:

248670

AF XY:

0.0526

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 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

African (AFR)

AF:

0.0350

AC:

1171

AN:

33472

American (AMR)

AF:

0.0624

AC:

2791

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0217

AC:

567

AN:

26132

East Asian (EAS)

AF:

0.206

AC:

8175

AN:

39698

South Asian (SAS)

AF:

0.0907

AC:

7819

AN:

86242

European-Finnish (FIN)

AF:

0.0368

AC:

1949

AN:

52892

Middle Eastern (MID)

AF:

0.0380

AC:

219

AN:

5764

European-Non Finnish (NFE)

AF:

0.0207

AC:

23065

AN:

1111596

Other (OTH)

AF:

0.0448

AC:

2702

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

2573

5146

7720

10293

12866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1054

2108

3162

4216

5270

<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:

0.0395

AC:

6012

AN:

152298

Hom.:

255

Cov.:

AF XY:

0.0434

AC XY:

3236

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0334

AC:

1390

AN:

41574

American (AMR)

AF:

0.0649

AC:

993

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3472

East Asian (EAS)

AF:

0.221

AC:

1143

AN:

5176

South Asian (SAS)

AF:

0.0921

AC:

445

AN:

4830

European-Finnish (FIN)

AF:

0.0407

AC:

432

AN:

10616

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0210

AC:

1429

AN:

68006

Other (OTH)

AF:

0.0402

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

282

564

846

1128

1410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0303

Hom.:

638

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

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (3)

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

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

GUCY2D-related recessive retinopathy (1)

Leber congenital amaurosis 1 (1)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

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

PhyloP100

2.9

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

Mutation Taster

=90/10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over