rs8069344

Variant names:

• chr17-8013961-T-A
• rs8069344
• NM_000180.4:c.2345T>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS2 BP4 BA1

This summary comes from the ClinGen Evidence Repository: The NM_000180.4(GUCY2D):c.2345T>A (p.Leu782His) variant is predicted to change the leucine at position p.782 to histidine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.3995, with 30227 alleles / 74954 total alleles in the African/African American 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 17920 adult individuals in gnomAD (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.119, which is below the ClinGen LCA / eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). 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, BS2, BP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8366093/MONDO:0100453/167

• Frequency:
  • Genomes: 𝑓 0.19 (4051 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13869 hom.)
• Consequence: GUCY2D NM_000180.4 missense
• Clinical Significance: Benign reviewed by expert panel B:10
• Conservation: PhyloP100: 2.36
• Publications: 29 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

ENSG00000279174 (HGNC:):

ACMG classification

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.

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.2345T>A	p.Leu782His	missense	Exon 12 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.2345T>A	p.Leu782His	missense	Exon 12 of 20	ENSP00000254854.4	Q02846
	ENSG00000279174	ENST00000623126.1	TSL:6	n.2418A>T		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29181 AN: 152088 Hom.: 4029 Cov.: 32

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.167

GnomAD2 exomes AF: 0.123 AC: 30853 AN: 251294 AF XY: 0.120

Gnomad AFR exome AF: 0.404

Gnomad AMR exome AF: 0.0602

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.127 AC: 185391 AN: 1461062 Hom.: 13869 Cov.: 32 AF XY: 0.126 AC XY: 91788 AN XY: 726852

African (AFR) AF: 0.408 AC: 13652 AN: 33448

American (AMR) AF: 0.0646 AC: 2888 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 3891 AN: 26132

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39698

South Asian (SAS) AF: 0.116 AC: 9988 AN: 86250

European-Finnish (FIN) AF: 0.121 AC: 6455 AN: 53256

Middle Eastern (MID) AF: 0.137 AC: 790 AN: 5768

European-Non Finnish (NFE) AF: 0.126 AC: 139636 AN: 1111416

Other (OTH) AF: 0.134 AC: 8071 AN: 60372

GnomAD4 genome AF: 0.192 AC: 29245 AN: 152206 Hom.: 4051 Cov.: 32 AF XY: 0.188 AC XY: 13972 AN XY: 74414

African (AFR) AF: 0.399 AC: 16575 AN: 41506

American (AMR) AF: 0.104 AC: 1588 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 529 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.118 AC: 571 AN: 4824

European-Finnish (FIN) AF: 0.114 AC: 1206 AN: 10610

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8305 AN: 68004

Other (OTH) AF: 0.166 AC: 350 AN: 2112

Alfa AF: 0.131 Hom.: 1172

Bravo AF: 0.199

TwinsUK AF: 0.129 AC: 477

ALSPAC AF: 0.129 AC: 498

ESP6500AA AF: 0.395 AC: 1740

ESP6500EA AF: 0.125 AC: 1078

ExAC AF: 0.130 AC: 15796

Asia WGS AF: 0.0870 AC: 306 AN: 3478

EpiCase AF: 0.120

EpiControl AF: 0.117

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Cone-rod dystrophy 6 (2)
-	-	2	not provided (2)
-	-	1	Choroidal dystrophy, central areolar, 1 (1)
-	-	1	Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1 (1)
-	-	1	GUCY2D-related recessive retinopathy (1)
-	-	1	Leber congenital amaurosis 1 (1)
-	-	1	Night blindness, congenital stationary, type1i (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.057	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.020	N
PhyloP100		2.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	2.0	N
REVEL	Benign	0.12
Sift	Benign	0.11	T
Sift4G	Uncertain	0.058	T
Polyphen		0.0	B
Vest4		0.052
MPC		0.28
ClinPred		0.0075	T
GERP RS		3.1
Varity_R		0.087
gMVP		0.52
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs8069344; hg19: chr17-7917279; COSMIC: COSV54694498; COSMIC: COSV54694498;