rs56034424

chr17-8006455-G-A

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.1119G>A(p.Val373=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,605,346 control chromosomes in the GnomAD database, including 460 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (35 hom., cov: 32)
  • Exomes 𝑓: 0.021 (425 hom.)
• Consequence: GUCY2D NM_000180.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.76

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 17-8006455-G-A is Benign according to our data. Variant chr17-8006455-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 471237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8006455-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.76 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUCY2D	NM_000180.4	c.1119G>A	p.Val373=	synonymous_variant	4/20	ENST00000254854.5
GUCY2D	XM_011523816.2	c.1119G>A	p.Val373=	synonymous_variant	3/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCY2D	ENST00000254854.5	c.1119G>A	p.Val373=	synonymous_variant	4/20	1	NM_000180.4	P1

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2888 AN: 152248 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.0593

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0452

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0226

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0197 AC: 4800 AN: 243046 Hom.: 73 AF XY: 0.0202 AC XY: 2669 AN XY: 132254

Gnomad AFR exome AF: 0.00382

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.0599

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00419

Gnomad FIN exome AF: 0.0402

Gnomad NFE exome AF: 0.0246

Gnomad OTH exome AF: 0.0312

GnomAD4 exome AF: 0.0208 AC: 30168 AN: 1452980 Hom.: 425 Cov.: 33 AF XY: 0.0207 AC XY: 14942 AN XY: 723230

Gnomad4 AFR exome AF: 0.00284

Gnomad4 AMR exome AF: 0.0146

Gnomad4 ASJ exome AF: 0.0569

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00446

Gnomad4 FIN exome AF: 0.0424

Gnomad4 NFE exome AF: 0.0215

Gnomad4 OTH exome AF: 0.0237

GnomAD4 genome AF: 0.0190 AC: 2888 AN: 152366 Hom.: 35 Cov.: 32 AF XY: 0.0198 AC XY: 1472 AN XY: 74516

Gnomad4 AFR AF: 0.00430

Gnomad4 AMR AF: 0.0236

Gnomad4 ASJ AF: 0.0593

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0452

Gnomad4 NFE AF: 0.0226

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0250 Hom.: 18

Bravo AF: 0.0170

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0288

EpiControl AF: 0.0286

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2021	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	5.1
Dann	Benign	0.63

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: rs56034424; hg19: chr17-7909773;