chr17-8014859-G-T

Position:

• chr17-8014859-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000180.4(GUCY2D):​c.2577G>T​(p.Pro859=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00382 in 1,614,102 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• 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 criteria provided, multiple submitters, no conflicts B:5
• 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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 17-8014859-G-T is Benign according to our data. Variant chr17-8014859-G-T is described in ClinVar as [Benign]. Clinvar id is 194323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00587 (893/152250) while in subpopulation SAS AF= 0.0485 (234/4820). AF 95% confidence interval is 0.0434. There are 14 homozygotes in gnomad4. There are 468 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUCY2D	NM_000180.4	c.2577G>T	p.Pro859=	splice_region_variant, synonymous_variant	14/20	ENST00000254854.5
GUCY2D	XM_011523816.2	c.2577G>T	p.Pro859=	splice_region_variant, synonymous_variant	13/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCY2D	ENST00000254854.5	c.2577G>T	p.Pro859=	splice_region_variant, synonymous_variant	14/20	1	NM_000180.4	P1
	ENST00000623126.1	n.1520C>A		non_coding_transcript_exon_variant	1/1

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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;