rs34598902

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000180.4(GUCY2D):c.2101C>T(p.Pro701Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0338 in 1,613,188 control chromosomes in the GnomAD database, including 2,099 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P701P) has been classified as Likely benign.

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/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 2.92

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000180.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0064867735).

BP6

Variant 17-8012594-C-T is Benign according to our data. Variant chr17-8012594-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 98558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8012594-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUCY2D	NM_000180.4 linkuse as main transcript	c.2101C>T	p.Pro701Ser	missense_variant	10/20	ENST00000254854.5
GUCY2D	XM_011523816.2 linkuse as main transcript	c.2101C>T	p.Pro701Ser	missense_variant	9/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCY2D	ENST00000254854.5 linkuse as main transcript	c.2101C>T	p.Pro701Ser	missense_variant	10/20	1	NM_000180.4	P1

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

GnomAD3 exomes

AF:

0.0527

AC:

13104

AN:

248670

Hom.:

683

AF XY:

0.0526

AC XY:

7088

AN XY:

134724

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 SAS exome

AF:

0.0897

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

Gnomad4 AFR exome

AF:

0.0350

Gnomad4 AMR exome

AF:

0.0624

Gnomad4 ASJ exome

AF:

0.0217

Gnomad4 EAS exome

AF:

0.206

Gnomad4 SAS exome

AF:

0.0907

Gnomad4 FIN exome

AF:

0.0368

Gnomad4 NFE exome

AF:

0.0207

Gnomad4 OTH exome

AF:

0.0448

GnomAD4 genome

AF:

0.0395

AC:

6012

AN:

152298

Hom.:

255

Cov.:

AF XY:

0.0434

AC XY:

3236

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0334

Gnomad4 AMR

AF:

0.0649

Gnomad4 ASJ

AF:

0.0222

Gnomad4 EAS

AF:

0.221

Gnomad4 SAS

AF:

0.0921

Gnomad4 FIN

AF:

0.0407

Gnomad4 NFE

AF:

0.0210

Gnomad4 OTH

AF:

0.0402

Alfa

AF:

0.0302

Hom.:

351

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

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 27884173, 11035546, 23424971, 20981092, 18055820, 15111605) -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 180/2178=8.2% -

Leber congenital amaurosis 1

Benign:1

Likely benign, no assertion criteria provided

research

Laboratory of Genetics in Ophthalmology, Institut Imagine

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

Cadd

Benign

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

MutationTaster

Benign

1.0

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over