Variant rs552184470 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000180.4(GUCY2D):c.129_134del(p.Leu44_Leu45del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00326 in 1,512,532 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L42L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 17 hom. )

Consequence

GUCY2D
NM_000180.4 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:7B:3

Conservation

PhyloP100: 4.32

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUCY2D	NM_000180.4 linkuse as main transcript	c.129_134del	p.Leu44_Leu45del	inframe_deletion	2/20	ENST00000254854.5
GUCY2D	XM_011523816.2 linkuse as main transcript	c.129_134del	p.Leu44_Leu45del	inframe_deletion	1/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCY2D	ENST00000254854.5 linkuse as main transcript	c.129_134del	p.Leu44_Leu45del	inframe_deletion	2/20	1	NM_000180.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

304

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00725

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00319

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00185

AC:

201

AN:

108698

Hom.:

AF XY:

0.00221

AC XY:

134

AN XY:

60574

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000751

Gnomad ASJ exome

AF:

0.000141

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00504

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00203

Gnomad OTH exome

AF:

0.00121

GnomAD4 exome

AF:

0.00340

AC:

4629

AN:

1360336

Hom.:

AF XY:

0.00354

AC XY:

2374

AN XY:

670956

show subpopulations

Gnomad4 AFR exome

AF:

0.000428

Gnomad4 AMR exome

AF:

0.00102

Gnomad4 ASJ exome

AF:

0.000207

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00630

Gnomad4 FIN exome

AF:

0.000276

Gnomad4 NFE exome

AF:

0.00365

Gnomad4 OTH exome

AF:

0.00310

GnomAD4 genome

AF:

0.00200

AC:

304

AN:

152196

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

127

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00726

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00319

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00183

Hom.:

Bravo

AF:

0.00209

Asia WGS

AF:

0.00174

AC:

AN:

3470

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:7Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2017	The c.129_134delTCTGCT variant in the GUCY2D gene has been reported previously in individuals with Leber congenital amaurosis or retinal dystrophy, but limited information was provided on the affected individuals (Stone et al., 2007; Sergouniotis et al., 2016). The c.129_134delTCTGCT variant causes an in-frame deletion of two Leucine residues starting at codon Leucine 44 amino acid, denoted p.Leu44_Leu45del. This amino acid deletion occurs at a position in a poly Leucine region that is not conserved. Reliable data is not available in large population cohorts to assess the frequency of the c.129_134delTCTGCT variant; however, it was observed in 176/63508 (0.277%) alleles from individuals undergoing testing at GeneDx (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.129_134delTCTGCT as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 13, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cone-rod dystrophy 6

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -

Leber congenital amaurosis 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Molecular Genetics, University of Zurich

Jan 30, 2021

- -

Choroidal dystrophy, central areolar, 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Likely pathogenic. This variant was inherited from a parent. -

Nystagmus;C0476397:Abnormal electroretinogram

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jul 11, 2014

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Jan 01, 2019

- -

GUCY2D-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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