17-8016436-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000180.4(GUCY2D):c.3225-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 1,556,222 control chromosomes in the GnomAD database, including 446 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 34 hom., cov: 33)

Exomes 𝑓: 0.021 ( 412 hom. )

Consequence

GUCY2D
NM_000180.4 splice_region, intron

Scores

Splicing: ADA: 0.00003757

Clinical Significance

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

Conservation

PhyloP100: -0.126

Publications

1 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: 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

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 17-8016436-C-T is Benign according to our data. Variant chr17-8016436-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0525 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2D	NM_000180.4	MANE Select	c.3225-7C>T		splice_region intron	N/A	NP_000171.1	Q02846

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GUCY2D	ENST00000254854.5	TSL:1 MANE Select	c.3225-7C>T	splice_region intron	N/A	ENSP00000254854.4	Q02846
GUCY2D	ENST00000574510.1	TSL:4	n.163-7C>T	splice_region intron	N/A
ENSG00000279174	ENST00000623126.1	TSL:6	n.-58G>A	upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.0188

AC:

2857

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00420

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0236

Gnomad ASJ

AF:

0.0594

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0447

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0223

Gnomad OTH

AF:

0.0306

GnomAD2 exomes

AF:

0.0205

AC:

3399

AN:

166208

AF XY:

0.0202

show subpopulations

Gnomad AFR exome

AF:

0.00420

Gnomad AMR exome

AF:

0.0140

Gnomad ASJ exome

AF:

0.0603

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0462

Gnomad NFE exome

AF:

0.0240

Gnomad OTH exome

AF:

0.0320

GnomAD4 exome

AF:

0.0206

AC:

28958

AN:

1403946

Hom.:

412

Cov.:

AF XY:

0.0205

AC XY:

14222

AN XY:

693826

show subpopulations

African (AFR)

AF:

0.00282

AC:

AN:

32282

American (AMR)

AF:

0.0157

AC:

581

AN:

37000

Ashkenazi Jewish (ASJ)

AF:

0.0569

AC:

1434

AN:

25220

East Asian (EAS)

AF:

0.0000270

AC:

AN:

37052

South Asian (SAS)

AF:

0.00439

AC:

351

AN:

79962

European-Finnish (FIN)

AF:

0.0444

AC:

2060

AN:

46436

Middle Eastern (MID)

AF:

0.0576

AC:

327

AN:

5678

European-Non Finnish (NFE)

AF:

0.0210

AC:

22753

AN:

1082060

Other (OTH)

AF:

0.0233

AC:

1360

AN:

58256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1434

2867

4301

5734

7168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

822

1644

2466

3288

4110

<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:

0.0188

AC:

2857

AN:

152276

Hom.:

Cov.:

AF XY:

0.0196

AC XY:

1462

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00419

AC:

174

AN:

41572

American (AMR)

AF:

0.0235

AC:

360

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0594

AC:

206

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00269

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0447

AC:

474

AN:

10612

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0223

AC:

1519

AN:

68024

Other (OTH)

AF:

0.0303

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

147

294

441

588

735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0200

Hom.:

Bravo

AF:

0.0167

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

ClinVar submissions

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

-0.78

CADD

Benign

6.6

(source)

DANN

Benign

0.93

PhyloP100

-0.13

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000038

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

Other links and lift over