17-8003060-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.13G>A​(p.Ala5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,373,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

GUCY2D
NM_000180.4 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.07

Publications

0 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=0.08394101).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GUCY2DNM_000180.4 linkc.13G>A p.Ala5Thr missense_variant Exon 2 of 20 ENST00000254854.5 NP_000171.1 Q02846
GUCY2DXM_011523816.2 linkc.13G>A p.Ala5Thr 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.13G>A p.Ala5Thr missense_variant Exon 2 of 20 1 NM_000180.4 ENSP00000254854.4 Q02846

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.0000233
AC:
32
AN:
1373764
Hom.:
0
Cov.:
32
AF XY:
0.0000251
AC XY:
17
AN XY:
677826
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
29818
American (AMR)
AF:
0.00
AC:
0
AN:
34778
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24866
East Asian (EAS)
AF:
0.00
AC:
0
AN:
34696
South Asian (SAS)
AF:
0.00
AC:
0
AN:
77490
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
33974
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5532
European-Non Finnish (NFE)
AF:
0.0000298
AC:
32
AN:
1075118
Other (OTH)
AF:
0.00
AC:
0
AN:
57492
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.442
Heterozygous variant carriers
0
2
4
6
8
10
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
Cov.:
33

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
Oct 30, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with GUCY2D-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces alanine with threonine at codon 5 of the GUCY2D protein (p.Ala5Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
9.3
DANN
Uncertain
0.99
DEOGEN2
Benign
0.096
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.0087
N
LIST_S2
Benign
0.46
T
M_CAP
Pathogenic
0.31
D
MetaRNN
Benign
0.084
T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
0.90
L
PhyloP100
-1.1
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-0.070
N
REVEL
Benign
0.10
Sift
Benign
0.48
T
Sift4G
Benign
0.69
T
Polyphen
0.0040
B
Vest4
0.17
MutPred
0.17
Gain of phosphorylation at A5 (P = 0.0154);
MVP
0.73
MPC
1.3
ClinPred
0.072
T
GERP RS
-0.98
PromoterAI
-0.020
Neutral
Varity_R
0.041
gMVP
0.49
Mutation Taster
=96/4
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: rs1975657312; hg19: chr17-7906378; API