rs786205500

Variant names:

• chr17-8003574-T-C
• rs786205500
• NM_000180.4:c.527T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_000180.4(GUCY2D):​c.527T>C​(p.Leu176Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L176F) has been classified as Uncertain significance. The gene GUCY2D is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GUCY2D NM_000180.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.67
• 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

Specifications for GUCY2D are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, cone-rod dystrophy, central areolar choroidal dystrophy, GUCY2D-related dominant retinopathy, cone-rod dystrophy 6, Leber congenital amaurosis, night blindness, congenital stationary, type1i, GUCY2D-related recessive retinopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 17-8003574-T-C is Pathogenic according to our data. Variant chr17-8003574-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 191070.Status of the report is criteria_provided_single_submitter, 1 stars.

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.527T>C	p.Leu176Pro	missense	Exon 2 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.527T>C	p.Leu176Pro	missense	Exon 2 of 20	ENSP00000254854.4	Q02846

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1430002 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 709912

African (AFR) AF: 0.00 AC: 0 AN: 32994

American (AMR) AF: 0.00 AC: 0 AN: 43456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25642

East Asian (EAS) AF: 0.00 AC: 0 AN: 38876

South Asian (SAS) AF: 0.00 AC: 0 AN: 83900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5426

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103514

Other (OTH) AF: 0.00 AC: 0 AN: 59362

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.95
MutPred		0.78		Loss of stability (P = 0.0274)
MVP		0.93
MPC		3.2
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.90
gMVP		0.93
Mutation Taster		=24/76	disease causing (ClinVar)

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: rs786205500; hg19: chr17-7906892;