17-8016515-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000180.4(GUCY2D):c.3297G>A(p.Pro1099Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,568,828 control chromosomes in the GnomAD database, including 439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1099P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.020 ( 34 hom., cov: 33)

Exomes 𝑓: 0.021 ( 405 hom. )

Consequence

GUCY2D
NM_000180.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -5.26

Publications

3 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:

ENSG00000279174 (HGNC:):

ENSG00000279174 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 17-8016515-G-A is Benign according to our data. Variant chr17-8016515-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.26 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0508 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2D	NM_000180.4	MANE Select	c.3297G>A	p.Pro1099Pro	synonymous	Exon 19 of 20	NP_000171.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GUCY2D	ENST00000254854.5	TSL:1 MANE Select	c.3297G>A	p.Pro1099Pro	synonymous	Exon 19 of 20	ENSP00000254854.4
GUCY2D	ENST00000574510.1	TSL:4	n.235G>A		non_coding_transcript_exon	Exon 2 of 2
ENSG00000279174	ENST00000623126.1	TSL:6	n.-137C>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.0198

AC:

3014

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00755

Gnomad AMI

AF:

0.0286

Gnomad AMR

AF:

0.0238

Gnomad ASJ

AF:

0.0594

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.0447

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0224

Gnomad OTH

AF:

0.0310

GnomAD2 exomes

AF:

0.0217

AC:

3724

AN:

171582

AF XY:

0.0215

show subpopulations

Gnomad AFR exome

AF:

0.00894

Gnomad AMR exome

AF:

0.0145

Gnomad ASJ exome

AF:

0.0609

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0491

Gnomad NFE exome

AF:

0.0253

Gnomad OTH exome

AF:

0.0331

GnomAD4 exome

AF:

0.0208

AC:

29420

AN:

1416600

Hom.:

405

Cov.:

AF XY:

0.0206

AC XY:

14455

AN XY:

701048

show subpopulations

African (AFR)

AF:

0.00641

AC:

209

AN:

32584

American (AMR)

AF:

0.0158

AC:

615

AN:

38898

Ashkenazi Jewish (ASJ)

AF:

0.0568

AC:

1443

AN:

25386

East Asian (EAS)

AF:

0.000106

AC:

AN:

37680

South Asian (SAS)

AF:

0.00493

AC:

399

AN:

80972

European-Finnish (FIN)

AF:

0.0446

AC:

2090

AN:

46858

Middle Eastern (MID)

AF:

0.0558

AC:

317

AN:

5680

European-Non Finnish (NFE)

AF:

0.0211

AC:

22958

AN:

1089890

Other (OTH)

AF:

0.0236

AC:

1385

AN:

58652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1570

3140

4709

6279

7849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

830

1660

2490

3320

4150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0198

AC:

3012

AN:

152228

Hom.:

Cov.:

AF XY:

0.0207

AC XY:

1538

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00753

AC:

313

AN:

41552

American (AMR)

AF:

0.0238

AC:

364

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0594

AC:

206

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00436

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0447

AC:

474

AN:

10596

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0224

AC:

1521

AN:

68004

Other (OTH)

AF:

0.0307

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

148

296

443

591

739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0241

Hom.:

Bravo

AF:

0.0177

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.010

(source)

DANN

Benign

0.78

PhyloP100

-5.3

Mutation Taster

=97/3

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over