17-8003090-G-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_000180.4(GUCY2D):​c.43G>A​(p.Gly15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,524,646 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G15G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

GUCY2D
NM_000180.4 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.70

Publications

1 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 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=0.082687885).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GUCY2DNM_000180.4 linkc.43G>A p.Gly15Arg missense_variant Exon 2 of 20 ENST00000254854.5 NP_000171.1 Q02846
GUCY2DXM_011523816.2 linkc.43G>A p.Gly15Arg missense_variant Exon 1 of 19 XP_011522118.1 Q02846

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GUCY2DENST00000254854.5 linkc.43G>A p.Gly15Arg missense_variant Exon 2 of 20 1 NM_000180.4 ENSP00000254854.4 Q02846

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152150
Hom.:
0
Cov.:
33
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000248
AC:
34
AN:
1372496
Hom.:
0
Cov.:
32
AF XY:
0.0000177
AC XY:
12
AN XY:
677086
show subpopulations
African (AFR)
AF:
0.0000336
AC:
1
AN:
29720
American (AMR)
AF:
0.00
AC:
0
AN:
34756
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24754
East Asian (EAS)
AF:
0.00
AC:
0
AN:
34608
South Asian (SAS)
AF:
0.0000259
AC:
2
AN:
77308
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
34144
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5224
European-Non Finnish (NFE)
AF:
0.0000279
AC:
30
AN:
1074586
Other (OTH)
AF:
0.0000174
AC:
1
AN:
57396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.00000657
AC:
1
AN:
152150
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74314
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41442
American (AMR)
AF:
0.00
AC:
0
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
67998
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1 Uncertain:1
Nov 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 15 of the GUCY2D protein (p.Gly15Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GUCY2D-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GUCY2D protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.094
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
0.36
DANN
Benign
0.81
DEOGEN2
Benign
0.087
T
Eigen
Benign
-2.2
Eigen_PC
Benign
-2.2
FATHMM_MKL
Benign
0.019
N
LIST_S2
Benign
0.35
T
M_CAP
Pathogenic
0.73
D
MetaRNN
Benign
0.083
T
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
0.0
N
PhyloP100
-1.7
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-0.18
N
REVEL
Benign
0.23
Sift
Benign
0.69
T
Sift4G
Benign
0.66
T
Polyphen
0.0
B
Vest4
0.085
MutPred
0.20
Gain of solvent accessibility (P = 0.0055);
MVP
0.36
MPC
1.5
ClinPred
0.041
T
GERP RS
-4.0
PromoterAI
-0.020
Neutral
Varity_R
0.039
gMVP
0.47
Mutation Taster
=94/6
polymorphism

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

Other links and lift over

dbSNP: rs954746846; hg19: chr17-7906408; API