rs56130505

chr17-8012602-G-Achr17-8012602-G-Cchr17-8012602-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000180.4(GUCY2D):c.2109G>A(p.Ala703=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0956 in 1,611,898 control chromosomes in the GnomAD database, including 8,406 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1137 hom., cov: 32)
  • Exomes 𝑓: 0.094 (7269 hom.)
• Consequence: GUCY2D NM_000180.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -6.01

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-8012602-G-A is Benign according to our data. Variant chr17-8012602-G-A is described in ClinVar as [Benign]. Clinvar id is 98559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8012602-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUCY2D	NM_000180.4	c.2109G>A	p.Ala703=	synonymous_variant	10/20	ENST00000254854.5
GUCY2D	XM_011523816.2	c.2109G>A	p.Ala703=	synonymous_variant	9/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCY2D	ENST00000254854.5	c.2109G>A	p.Ala703=	synonymous_variant	10/20	1	NM_000180.4	P1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16571 AN: 152044 Hom.: 1133 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0508

Gnomad ASJ AF: 0.0669

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0394

Gnomad FIN AF: 0.0682

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0981

Gnomad OTH AF: 0.0813

GnomAD3 exomes AF: 0.0757 AC: 18736 AN: 247652 Hom.: 985 AF XY: 0.0739 AC XY: 9923 AN XY: 134298

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.0349

Gnomad ASJ exome AF: 0.0617

Gnomad EAS exome AF: 0.000437

Gnomad SAS exome AF: 0.0412

Gnomad FIN exome AF: 0.0782

Gnomad NFE exome AF: 0.0955

Gnomad OTH exome AF: 0.0688

GnomAD4 exome AF: 0.0942 AC: 137548 AN: 1459736 Hom.: 7269 Cov.: 33 AF XY: 0.0926 AC XY: 67258 AN XY: 726172

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.0365

Gnomad4 ASJ exome AF: 0.0618

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0419

Gnomad4 FIN exome AF: 0.0781

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.0877

GnomAD4 genome AF: 0.109 AC: 16596 AN: 152162 Hom.: 1137 Cov.: 32 AF XY: 0.105 AC XY: 7788 AN XY: 74374

Gnomad4 AFR AF: 0.187

Gnomad4 AMR AF: 0.0506

Gnomad4 ASJ AF: 0.0669

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.0394

Gnomad4 FIN AF: 0.0682

Gnomad4 NFE AF: 0.0981

Gnomad4 OTH AF: 0.0804

Alfa AF: 0.0960 Hom.: 385

Bravo AF: 0.111

Asia WGS AF: 0.0250 AC: 90 AN: 3478

EpiCase AF: 0.0881

EpiControl AF: 0.0858

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

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. -
not provided, no classification provided	literature only	Retina International	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.29
Dann	Benign	0.62

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: rs56130505; hg19: chr17-7915920; COSMIC: COSV54698484; COSMIC: COSV54698484;