rs764072081

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2BP4_StrongBP6_Moderate

The NM_000180.4(GUCY2D):c.11G>A(p.Cys4Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000642 in 1,526,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

GUCY2D
NM_000180.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.809

Publications

2 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: Likely_benign. The variant received -5 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 55 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 0.78087 (below the threshold of 3.09). Trascript score misZ: 0.0082692 (below the threshold of 3.09). GenCC associations: The gene is linked to Leber congenital amaurosis 1, GUCY2D-related dominant retinopathy, central areolar choroidal dystrophy, cone-rod dystrophy, cone-rod dystrophy 6, night blindness, congenital stationary, type1i, GUCY2D-related recessive retinopathy, Leber congenital amaurosis.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066908).

BP6

Variant 17-8003058-G-A is Benign according to our data. Variant chr17-8003058-G-A is described in ClinVar as [Benign]. Clinvar id is 2045171.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2D	NM_000180.4 link	c.11G>A	p.Cys4Tyr	missense_variant	Exon 2 of 20	ENST00000254854.5	NP_000171.1	Q02846
GUCY2D	XM_011523816.2 link	c.11G>A	p.Cys4Tyr	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.11G>A	p.Cys4Tyr	missense_variant	Exon 2 of 20	1	NM_000180.4	ENSP00000254854.4		Q02846

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00367

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000533

AC:

AN:

118186

AF XY:

0.000568

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00677

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000575

AC:

AN:

1374164

Hom.:

Cov.:

AF XY:

0.0000590

AC XY:

AN XY:

678024

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29852

American (AMR)

AF:

0.00

AC:

AN:

34834

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24858

East Asian (EAS)

AF:

0.00204

AC:

AN:

34726

South Asian (SAS)

AF:

0.00

AC:

AN:

77528

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33972

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5578

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075294

Other (OTH)

AF:

0.000139

AC:

AN:

57522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000125

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00368

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000208

ExAC

AF:

0.0000320

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Jun 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.10

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.0067

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.9

PhyloP100

0.81

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.68

REVEL

Benign

0.19

Sift

Benign

0.31

Sift4G

Benign

0.52

Polyphen

0.047

Vest4

0.34

MVP

0.78

MPC

2.0

ClinPred

0.038

GERP RS

4.0

PromoterAI

0.036

Neutral

(source)

Varity_R

0.17

gMVP

0.62

Mutation Taster

=83/17

polymorphism

(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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rs764072081

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