17-8006707-C-T

Variant names:

• chr17-8006707-C-T
• rs55916957
• NM_000180.4:c.1371C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BS2 BP4 BA1 BP7

This summary comes from the ClinGen Evidence Repository: NM_000180.4(GUCY2D):c.1371C>T (p.Cys457=) is a synonymous variant in exon 4 of 20. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.1129, with 5137 alleles/44460 total alleles and 134 homozygotes in the East Asian population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.016. (BA1). This variant has been found in the homozygous state in 325 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL has no data as this is a synonymous variant. The splicing impact predictor SpliceAI gives a delta score of 0.02, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BP4, BP7. (VCEP specifications version 1.0.0; date of approval 01/22/2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA202700/MONDO:0100453/167

• Frequency:
  • Genomes: 𝑓 0.0049 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (291 hom.)
• Consequence: GUCY2D NM_000180.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 1.50

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 -14 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2D	NM_000180.4	c.1371C>T	p.Cys457Cys	synonymous_variant	Exon 4 of 20	ENST00000254854.5	NP_000171.1
GUCY2D	XM_011523816.2	c.1371C>T	p.Cys457Cys	synonymous_variant	Exon 3 of 19		XP_011522118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5	c.1371C>T	p.Cys457Cys	synonymous_variant	Exon 4 of 20	1	NM_000180.4	ENSP00000254854.4

Frequencies

GnomAD3 genomes AF: 0.00492 AC: 749 AN: 152216 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.0101 AC: 2330 AN: 229692 Hom.: 128 AF XY: 0.00922 AC XY: 1154 AN XY: 125164

Gnomad AFR exome AF: 0.00169

Gnomad AMR exome AF: 0.00192

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.00256

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00540

GnomAD4 exome AF: 0.00388 AC: 5634 AN: 1452372 Hom.: 291 Cov.: 33 AF XY: 0.00380 AC XY: 2741 AN XY: 721822

Gnomad4 AFR exome AF: 0.000661

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.00471

Gnomad4 EAS exome AF: 0.115

Gnomad4 SAS exome AF: 0.00315

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.00839

GnomAD4 genome AF: 0.00488 AC: 744 AN: 152334 Hom.: 34 Cov.: 32 AF XY: 0.00571 AC XY: 425 AN XY: 74492

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00120 Hom.: 2

Bravo AF: 0.00610

Asia WGS AF: 0.0510 AC: 180 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Feb 25, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GUCY2D-related recessive retinopathy Benign:1

Jan 30, 2025

ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

NM_000180.4(GUCY2D):c.1371C>T (p.Cys457=) is a synonymous variant in exon 4 of 20. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.1129, with 5137 alleles/44460 total alleles and 134 homozygotes in the East Asian population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.016. (BA1). This variant has been found in the homozygous state in 325 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL has no data as this is a synonymous variant. The splicing impact predictor SpliceAI gives a delta score of 0.02, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BP4, BP7. (VCEP specifications version 1.0.0; date of approval 01/22/2025) -

Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1;C4551884:Choroidal dystrophy, central areolar, 1;C5231408:Night blindness, congenital stationary, type1i Benign:1

Jan 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs55916957; hg19: chr17-7910025;