rs3829789

Positions:

• chr17-8003871-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000180.4(GUCY2D):​c.741C>T​(p.His247His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,612,768 control chromosomes in the GnomAD database, including 13,568 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (999 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12569 hom.)
• Consequence: GUCY2D NM_000180.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.400

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 17-8003871-C-T is Benign according to our data. Variant chr17-8003871-C-T is described in ClinVar as [Benign]. Clinvar id is 92582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8003871-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCY2D	NM_000180.4	c.741C>T	p.His247His	synonymous_variant	3/20	ENST00000254854.5	NP_000171.1
GUCY2D	XM_011523816.2	c.741C>T	p.His247His	synonymous_variant	2/19		XP_011522118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5	c.741C>T	p.His247His	synonymous_variant	3/20	1	NM_000180.4	ENSP00000254854.4

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16549 AN: 152124 Hom.: 999 Cov.: 32

Gnomad AFR AF: 0.0725

Gnomad AMI AF: 0.0484

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.0602

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.0967

GnomAD3 exomes AF: 0.118 AC: 29372 AN: 248952 Hom.: 1874 AF XY: 0.118 AC XY: 15988 AN XY: 135010

Gnomad AFR exome AF: 0.0749

Gnomad AMR exome AF: 0.0930

Gnomad ASJ exome AF: 0.0632

Gnomad EAS exome AF: 0.208

Gnomad SAS exome AF: 0.115

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.128 AC: 187667 AN: 1460526 Hom.: 12569 Cov.: 36 AF XY: 0.128 AC XY: 93245 AN XY: 726628

Gnomad4 AFR exome AF: 0.0741

Gnomad4 AMR exome AF: 0.0920

Gnomad4 ASJ exome AF: 0.0620

Gnomad4 EAS exome AF: 0.195

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.133

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.109 AC: 16555 AN: 152242 Hom.: 999 Cov.: 32 AF XY: 0.109 AC XY: 8147 AN XY: 74436

Gnomad4 AFR AF: 0.0726

Gnomad4 AMR AF: 0.100

Gnomad4 ASJ AF: 0.0602

Gnomad4 EAS AF: 0.216

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.0967

Alfa AF: 0.113 Hom.: 526

Bravo AF: 0.107

Asia WGS AF: 0.164 AC: 570 AN: 3478

EpiCase AF: 0.114

EpiControl AF: 0.112

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.3
DANN	Benign	0.95

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

Other links and lift over

dbSNP: rs3829789; hg19: chr17-7907189; COSMIC: COSV54694323;