rs9905402

Positions:

• chr17-8003108-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000180.4(GUCY2D):​c.61T>C​(p.Trp21Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0402 in 1,521,538 control chromosomes in the GnomAD database, including 3,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (1514 hom., cov: 33)
  • Exomes 𝑓: 0.034 (2079 hom.)
• Consequence: GUCY2D NM_000180.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.241

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002603203).
• BP6: Variant 17-8003108-T-C is Benign according to our data. Variant chr17-8003108-T-C is described in ClinVar as [Benign]. Clinvar id is 92581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8003108-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCY2D	NM_000180.4	c.61T>C	p.Trp21Arg	missense_variant	2/20	ENST00000254854.5	NP_000171.1
GUCY2D	XM_011523816.2	c.61T>C	p.Trp21Arg	missense_variant	1/19		XP_011522118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5	c.61T>C	p.Trp21Arg	missense_variant	2/20	1	NM_000180.4	ENSP00000254854.4

Frequencies

GnomAD3 genomes AF: 0.0961 AC: 14595 AN: 151950 Hom.: 1500 Cov.: 33

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0697

Gnomad ASJ AF: 0.0625

Gnomad EAS AF: 0.0310

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.0216

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0224

Gnomad OTH AF: 0.0748

GnomAD3 exomes AF: 0.0480 AC: 5516 AN: 114956 Hom.: 258 AF XY: 0.0504 AC XY: 3202 AN XY: 63542

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.0449

Gnomad ASJ exome AF: 0.0482

Gnomad EAS exome AF: 0.0225

Gnomad SAS exome AF: 0.104

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.0216

Gnomad OTH exome AF: 0.0405

GnomAD4 exome AF: 0.0340 AC: 46528 AN: 1369480 Hom.: 2079 Cov.: 32 AF XY: 0.0355 AC XY: 23977 AN XY: 675380

Gnomad4 AFR exome AF: 0.259

Gnomad4 AMR exome AF: 0.0491

Gnomad4 ASJ exome AF: 0.0509

Gnomad4 EAS exome AF: 0.0109

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.0194

Gnomad4 NFE exome AF: 0.0216

Gnomad4 OTH exome AF: 0.0513

GnomAD4 genome AF: 0.0964 AC: 14652 AN: 152058 Hom.: 1514 Cov.: 33 AF XY: 0.0957 AC XY: 7114 AN XY: 74342

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.0697

Gnomad4 ASJ AF: 0.0625

Gnomad4 EAS AF: 0.0307

Gnomad4 SAS AF: 0.123

Gnomad4 FIN AF: 0.0216

Gnomad4 NFE AF: 0.0224

Gnomad4 OTH AF: 0.0750

Alfa AF: 0.0472 Hom.: 103

Bravo AF: 0.102

ESP6500AA AF: 0.117 AC: 278

ESP6500EA AF: 0.0120 AC: 65

ExAC AF: 0.0261 AC: 1225

Asia WGS AF: 0.110 AC: 384 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2019	This variant is associated with the following publications: (PMID: 24066033, 27884173, 16123401, 20981092, 18055820, 15111605) -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2016	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.3
DANN	Benign	0.47
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00032	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.14
Sift	Benign	0.90	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.041
MutPred		0.64		Gain of methylation at W21 (P = 0.0095);
MPC		2.1
ClinPred		0.000022	T
GERP RS		0.63
Varity_R		0.048
gMVP		0.42

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: rs9905402; hg19: chr17-7906426; COSMIC: COSV54697450;