chr17-8003354-G-T

Variant names:

• chr17-8003354-G-T
• rs61749668
• NM_000180.4:c.307G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000180.4(GUCY2D):​c.307G>T​(p.Glu103*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000152 in 1,317,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E103E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay. The gene GUCY2D is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: GUCY2D NM_000180.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.79
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.307G>T	p.Glu103*	stop_gained	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.307G>T	p.Glu103*	stop_gained	Exon 2 of 20	ENSP00000254854.4	Q02846

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000152 AC: 2 AN: 1317544 Hom.: 0 Cov.: 34 AF XY: 0.00000308 AC XY: 2 AN XY: 649942

African (AFR) AF: 0.00 AC: 0 AN: 26276

American (AMR) AF: 0.00 AC: 0 AN: 25500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22662

East Asian (EAS) AF: 0.00 AC: 0 AN: 29140

South Asian (SAS) AF: 0.00 AC: 0 AN: 71998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4044

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1049644

Other (OTH) AF: 0.00 AC: 0 AN: 54474

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		6.8
Vest4		0.73
GERP RS		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61749668; hg19: chr17-7906672;