rs61749665

Positions:

chr17-8003201-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000180.4(GUCY2D):c.154G>T(p.Ala52Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 1,517,162 control chromosomes in the GnomAD database, including 95,479 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 8439 hom., cov: 33)

Exomes 𝑓: 0.34 ( 87040 hom. )

Consequence

GUCY2D
NM_000180.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:13O:1

Conservation

PhyloP100: -0.508

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.106682E-6).

BP6

Variant 17-8003201-G-T is Benign according to our data. Variant chr17-8003201-G-T is described in ClinVar as [Benign]. Clinvar id is 9353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8003201-G-T is described in Lovd as [Benign]. Variant chr17-8003201-G-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCY2D	NM_000180.4 linkuse as main transcript	c.154G>T	p.Ala52Ser	missense_variant	2/20	ENST00000254854.5	NP_000171.1	Q02846
GUCY2D	XM_011523816.2 linkuse as main transcript	c.154G>T	p.Ala52Ser	missense_variant	1/19		XP_011522118.1	Q02846

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5 linkuse as main transcript	c.154G>T	p.Ala52Ser	missense_variant	2/20	1	NM_000180.4	ENSP00000254854.4		Q02846

Frequencies

GnomAD3 genomes

AF:

0.311

AC:

47231

AN:

151842

Hom.:

8437

Cov.:

show subpopulations

Gnomad AFR

AF:

0.166

Gnomad AMI

AF:

0.341

Gnomad AMR

AF:

0.384

Gnomad ASJ

AF:

0.337

Gnomad EAS

AF:

0.679

Gnomad SAS

AF:

0.584

Gnomad FIN

AF:

0.411

Gnomad MID

AF:

0.341

Gnomad NFE

AF:

0.319

Gnomad OTH

AF:

0.312

GnomAD3 exomes

AF:

0.416

AC:

46515

AN:

111840

Hom.:

10854

AF XY:

0.426

AC XY:

26486

AN XY:

62234

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.434

Gnomad ASJ exome

AF:

0.332

Gnomad EAS exome

AF:

0.695

Gnomad SAS exome

AF:

0.582

Gnomad FIN exome

AF:

0.402

Gnomad NFE exome

AF:

0.312

Gnomad OTH exome

AF:

0.356

GnomAD4 exome

AF:

0.345

AC:

470659

AN:

1365212

Hom.:

87040

Cov.:

AF XY:

0.351

AC XY:

236627

AN XY:

673498

show subpopulations

Gnomad4 AFR exome

AF:

0.158

Gnomad4 AMR exome

AF:

0.429

Gnomad4 ASJ exome

AF:

0.328

Gnomad4 EAS exome

AF:

0.695

Gnomad4 SAS exome

AF:

0.579

Gnomad4 FIN exome

AF:

0.404

Gnomad4 NFE exome

AF:

0.317

Gnomad4 OTH exome

AF:

0.357

GnomAD4 genome

AF:

0.311

AC:

47235

AN:

151950

Hom.:

8439

Cov.:

AF XY:

0.323

AC XY:

24004

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.166

Gnomad4 AMR

AF:

0.384

Gnomad4 ASJ

AF:

0.337

Gnomad4 EAS

AF:

0.679

Gnomad4 SAS

AF:

0.582

Gnomad4 FIN

AF:

0.411

Gnomad4 NFE

AF:

0.319

Gnomad4 OTH

AF:

0.317

Alfa

AF:

0.313

Hom.:

2204

Bravo

AF:

0.297

TwinsUK

AF:

0.318

AC:

1179

ALSPAC

AF:

0.328

AC:

1264

ESP6500AA

AF:

0.126

AC:

396

ESP6500EA

AF:

0.243

AC:

1601

ExAC

AF:

0.295

AC:

22211

Asia WGS

AF:

0.596

AC:

2061

AN:

3466

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:4Other:1

Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Leber congenital amaurosis 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1998

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Cone-rod dystrophy 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Oct 04, 2021

Population allele frequency is 40% (rs61749665, 54,832/138,790 alleles in gnomAD v2.0.2). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria met: BA1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

2.0

DANN

Benign

0.86

DEOGEN2

Benign

0.12

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0000021

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.4

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.85

REVEL

Benign

0.13

Sift

Benign

0.20

Sift4G

Benign

0.28

Polyphen

0.17

Vest4

0.040

MPC

1.2

ClinPred

0.0024

GERP RS

0.19

Varity_R

0.052

gMVP

0.30

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