17-8014859-G-T

Variant names:

• chr17-8014859-G-T
• rs112372281
• NM_000180.4:c.2577G>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BS2 BA1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000180.4(GUCY2D):c.2577G>T (p.Pro859=) variant is located at the first base of exon 14 and does not alter the amino acid (proline) at position p.859. The splicing impact predictor SpliceAI gives a delta score of 0.03, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.04139, with 3871 alleles / 91074 total alleles in the South 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 141 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). 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, BS2, BP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA201118/MONDO:0100453/167

• Frequency:
  • Genomes: 𝑓 0.0059 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (127 hom.)
• Consequence: GUCY2D NM_000180.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.7349
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 0.332

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]

ENSG00000279174 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: 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.2577G>T	p.Pro859Pro	splice_region_variant, synonymous_variant	Exon 14 of 20	ENST00000254854.5	NP_000171.1
GUCY2D	XM_011523816.2	c.2577G>T	p.Pro859Pro	splice_region_variant, synonymous_variant	Exon 13 of 19		XP_011522118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5	c.2577G>T	p.Pro859Pro	splice_region_variant, synonymous_variant	Exon 14 of 20	1	NM_000180.4	ENSP00000254854.4
ENSG00000279174	ENST00000623126.1	n.1520C>A		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.00581 AC: 884 AN: 152132 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0481

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00679 AC: 1707 AN: 251356 Hom.: 45 AF XY: 0.00834 AC XY: 1133 AN XY: 135872

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0428

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000634

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00360 AC: 5265 AN: 1461852 Hom.: 127 Cov.: 35 AF XY: 0.00470 AC XY: 3420 AN XY: 727228

Gnomad4 AFR exome AF: 0.0155

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00295

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0422

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000587

Gnomad4 OTH exome AF: 0.00517

GnomAD4 genome AF: 0.00587 AC: 893 AN: 152250 Hom.: 14 Cov.: 32 AF XY: 0.00629 AC XY: 468 AN XY: 74446

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0485

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.00516

Asia WGS AF: 0.0310 AC: 109 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

May 13, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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

The NM_000180.4(GUCY2D):c.2577G>T (p.Pro859=) variant is located at the first base of exon 14 and does not alter the amino acid (proline) at position p.859. The splicing impact predictor SpliceAI gives a delta score of 0.03, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.04139, with 3871 alleles / 91074 total alleles in the South 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 141 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). 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, BS2, BP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.73
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.030		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: rs112372281; hg19: chr17-7918177;