rs140638938

chr17-8006651-G-Achr17-8006651-G-Cchr17-8006651-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000180.4(GUCY2D):c.1315G>A(p.Gly439Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,612,710 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G439W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (3 hom.)
• Consequence: GUCY2D NM_000180.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.98

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15413344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUCY2D	NM_000180.4	c.1315G>A	p.Gly439Arg	missense_variant	4/20	ENST00000254854.5
GUCY2D	XM_011523816.2	c.1315G>A	p.Gly439Arg	missense_variant	3/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCY2D	ENST00000254854.5	c.1315G>A	p.Gly439Arg	missense_variant	4/20	1	NM_000180.4	P1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152218 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000369 AC: 90 AN: 244094 Hom.: 1 AF XY: 0.000513 AC XY: 68 AN XY: 132550

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000156

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000182 AC: 266 AN: 1460374 Hom.: 3 Cov.: 33 AF XY: 0.000286 AC XY: 208 AN XY: 726320

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00213

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152336 Hom.: 1 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74490

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000143 Hom.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.000218

EpiControl AF: 0.000357

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Choroidal dystrophy, central areolar, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Uncertain significance. This variant was inherited from a parent. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 31, 2016

- -

Nystagmus;C0476397:Abnormal electroretinogram Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jul 11, 2014

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.90	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.34		Gain of solvent accessibility (P = 0.0097);
MVP		0.91
MPC		0.86
ClinPred		0.24	T
GERP RS		5.0
Varity_R		0.18
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140638938; hg19: chr17-7909969;