Genetic Variant GUCY2D:c.-9-128C>T (chr17-8002911-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_000180.4(GUCY2D):c.-9-128C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000735 in 543,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000074 ( 0 hom. )

Consequence

GUCY2D
NM_000180.4 intron

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.0220

Publications

0 publications found

Variant links:

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: Orphanet, G2P
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

GUCY2D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 17-8002911-C-T is Benign according to our data. Variant chr17-8002911-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3033577.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2D	NM_000180.4 link	c.-9-128C>T		intron_variant	Intron 1 of 19	ENST00000254854.5	NP_000171.1	Q02846
GUCY2D	XM_011523816.2 link	c.-137C>T		upstream_gene_variant			XP_011522118.1	Q02846

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5 link	c.-9-128C>T		intron_variant	Intron 1 of 19	1	NM_000180.4	ENSP00000254854.4		Q02846

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000735

AC:

AN:

543868

Hom.:

AF XY:

0.00000714

AC XY:

AN XY:

279984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

11474

American (AMR)

AF:

0.00

AC:

AN:

15474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14010

East Asian (EAS)

AF:

0.00

AC:

AN:

24722

South Asian (SAS)

AF:

0.00

AC:

AN:

44332

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3652

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

371646

Other (OTH)

AF:

0.00

AC:

AN:

28728

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

GUCY2D-related disorder

Benign:1

Jul 04, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

0.022

PromoterAI

-0.050

Neutral

(source)

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

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chr17-8002911-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over