17-8006651-G-T

Variant names:

• chr17-8006651-G-T
• rs140638938
• NM_000180.4:c.1315G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP2 PP3_Moderate

The NM_000180.4(GUCY2D):​c.1315G>T​(p.Gly439Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,460,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G439R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: GUCY2D NM_000180.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98
• Publications: 2 publications found

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]

GUCY2D Gene-Disease associations (from GenCC):

• cone-rod dystrophy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• GUCY2D-related dominant retinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• GUCY2D-related recessive retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leber congenital amaurosis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• night blindness, congenital stationary, type1i

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• central areolar choroidal dystrophy

  Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 55 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 0.78087 (below the threshold of 3.09). Trascript score misZ: 0.0082692 (below the threshold of 3.09). GenCC associations: The gene is linked to Leber congenital amaurosis 1, GUCY2D-related dominant retinopathy, central areolar choroidal dystrophy, cone-rod dystrophy, cone-rod dystrophy 6, night blindness, congenital stationary, type1i, GUCY2D-related recessive retinopathy, Leber congenital amaurosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000180.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2D	NM_000180.4	MANE Select	c.1315G>T	p.Gly439Trp	missense	Exon 4 of 20	NP_000171.1	Q02846

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2D	ENST00000254854.5	TSL:1 MANE Select	c.1315G>T	p.Gly439Trp	missense	Exon 4 of 20	ENSP00000254854.4	Q02846

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460376 Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4 AN XY: 726322

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111464

Other (OTH) AF: 0.0000166 AC: 1 AN: 60310

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		3.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.44		Gain of solvent accessibility (P = 0.0039)
MVP		0.90
MPC		0.91
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.21
gMVP		0.80
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs140638938; hg19: chr17-7909969;