chr17-8015920-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS2BA1BP4

This summary comes from the ClinGen Evidence Repository: The variant NM_000180.4(GUCY2D):c.3044-7G>T is located in intron 16. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.04452, with 52,788 alleles / 1,177,142 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.016 (BA1). This variant has been found in the homozygous state in >6 adult individuals in gnomAD (1363 individuals, gnomAD version 4.1.0; BS2). In addition, the splicing impact predictor SpliceAI gives a delta score of 0.04, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8366302/MONDO:0100453/167

Frequency

Genomes: 𝑓 0.028 ( 97 hom., cov: 33)

Exomes 𝑓: 0.038 ( 1266 hom. )

Consequence

GUCY2D
NM_000180.4 splice_region, intron

Scores

Splicing: ADA: 0.00003016

Clinical Significance

Benign reviewed by expert panel B:5

Conservation

PhyloP100: -1.39

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 -13 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2D	NM_000180.4 link	c.3044-7G>T		splice_region_variant, intron_variant	Intron 16 of 19	ENST00000254854.5	NP_000171.1	Q02846
GUCY2D	XM_011523816.2 link	c.3044-7G>T		splice_region_variant, intron_variant	Intron 15 of 18		XP_011522118.1	Q02846

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GUCY2D	ENST00000254854.5 link	c.3044-7G>T	splice_region_variant, intron_variant	Intron 16 of 19	1	NM_000180.4	ENSP00000254854.4	Q02846
ENSG00000279174	ENST00000623126.1 link	n.459C>A	non_coding_transcript_exon_variant	Exon 1 of 1	6
ENSG00000299408	ENST00000763246.1 link	n.146+12C>A	intron_variant	Intron 2 of 2
GUCY2D	ENST00000574510.1 link	n.-209G>T	upstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0281

AC:

4269

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00799

Gnomad AMI

AF:

0.119

Gnomad AMR

AF:

0.0226

Gnomad ASJ

AF:

0.0487

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.0170

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0444

Gnomad OTH

AF:

0.0330

GnomAD2 exomes

AF:

0.0279

AC:

6685

AN:

239362

AF XY:

0.0286

show subpopulations

Gnomad AFR exome

AF:

0.00727

Gnomad AMR exome

AF:

0.0157

Gnomad ASJ exome

AF:

0.0496

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0188

Gnomad NFE exome

AF:

0.0449

Gnomad OTH exome

AF:

0.0305

GnomAD4 exome

AF:

0.0383

AC:

55744

AN:

1455586

Hom.:

1266

Cov.:

AF XY:

0.0378

AC XY:

27327

AN XY:

723614

show subpopulations

African (AFR)

AF:

0.00620

AC:

207

AN:

33402

American (AMR)

AF:

0.0173

AC:

763

AN:

44004

Ashkenazi Jewish (ASJ)

AF:

0.0487

AC:

1263

AN:

25948

East Asian (EAS)

AF:

0.0000760

AC:

AN:

39490

South Asian (SAS)

AF:

0.00634

AC:

541

AN:

85306

European-Finnish (FIN)

AF:

0.0201

AC:

1052

AN:

52430

Middle Eastern (MID)

AF:

0.0321

AC:

185

AN:

5762

European-Non Finnish (NFE)

AF:

0.0449

AC:

49767

AN:

1109138

Other (OTH)

AF:

0.0327

AC:

1963

AN:

60106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2863

5727

8590

11454

14317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1786

3572

5358

7144

8930

<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:

0.0280

AC:

4265

AN:

152294

Hom.:

Cov.:

AF XY:

0.0269

AC XY:

2004

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00794

AC:

330

AN:

41574

American (AMR)

AF:

0.0226

AC:

346

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0487

AC:

169

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00538

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0170

AC:

181

AN:

10624

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0444

AC:

3021

AN:

68004

Other (OTH)

AF:

0.0326

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

216

431

647

862

1078

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0312

Hom.:

Bravo

AF:

0.0276

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GUCY2D-related recessive retinopathy

Benign:1

Jan 30, 2025

ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The variant NM_000180.4(GUCY2D):c.3044-7G>T is located in intron 16. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.04452, with 52,788 alleles / 1,177,142 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.016 (BA1). This variant has been found in the homozygous state in >6 adult individuals in gnomAD (1363 individuals, gnomAD version 4.1.0; BS2). In addition, the splicing impact predictor SpliceAI gives a delta score of 0.04, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.7

(source)

DANN

Benign

0.86

PhyloP100

-1.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000030

dbscSNV1_RF

Benign

0.0080

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over