rs61749665

Variant names:

• chr17-8003201-G-T
• rs61749665
• NM_000180.4:c.154G>T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000180.4(GUCY2D):c.154G>T (p.Ala52Ser) variant is predicted to replace the alanine at position p.52 with serine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.6857, with 26306 alleles / 37974 total alleles in the East Asian 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 95,479 adult individuals in gnomAD v4.1.0 (BS2). The computational predictor REVEL gives a score of 0.126, 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 0.0, 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/CA145842/MONDO:0100453/167

• Frequency:
  • Genomes: 𝑓 0.31 (8439 hom., cov: 33)
  • Exomes 𝑓: 0.34 (87040 hom.)
• Consequence: GUCY2D NM_000180.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 B:15 O:1
• Conservation: PhyloP100: -0.508
• Publications: 24 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: 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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2D	NM_000180.4	MANE Select	c.154G>T	p.Ala52Ser	missense	Exon 2 of 20	NP_000171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2D	ENST00000254854.5	TSL:1 MANE Select	c.154G>T	p.Ala52Ser	missense	Exon 2 of 20	ENSP00000254854.4

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47231 AN: 151842 Hom.: 8437 Cov.: 33

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.341

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.679

Gnomad SAS AF: 0.584

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.312

GnomAD2 exomes AF: 0.416 AC: 46515 AN: 111840 AF XY: 0.426

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.434

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.695

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.356

GnomAD4 exome AF: 0.345 AC: 470659 AN: 1365212 Hom.: 87040 Cov.: 36 AF XY: 0.351 AC XY: 236627 AN XY: 673498

African (AFR) AF: 0.158 AC: 4415 AN: 28014

American (AMR) AF: 0.429 AC: 14459 AN: 33690

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 7952 AN: 24230

East Asian (EAS) AF: 0.695 AC: 22838 AN: 32864

South Asian (SAS) AF: 0.579 AC: 44239 AN: 76354

European-Finnish (FIN) AF: 0.404 AC: 15500 AN: 38390

Middle Eastern (MID) AF: 0.324 AC: 1452 AN: 4476

European-Non Finnish (NFE) AF: 0.317 AC: 339518 AN: 1070330

Other (OTH) AF: 0.357 AC: 20286 AN: 56864

GnomAD4 genome AF: 0.311 AC: 47235 AN: 151950 Hom.: 8439 Cov.: 33 AF XY: 0.323 AC XY: 24004 AN XY: 74256

African (AFR) AF: 0.166 AC: 6875 AN: 41508

American (AMR) AF: 0.384 AC: 5865 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1167 AN: 3468

East Asian (EAS) AF: 0.679 AC: 3468 AN: 5110

South Asian (SAS) AF: 0.582 AC: 2808 AN: 4822

European-Finnish (FIN) AF: 0.411 AC: 4347 AN: 10564

Middle Eastern (MID) AF: 0.318 AC: 93 AN: 292

European-Non Finnish (NFE) AF: 0.319 AC: 21633 AN: 67892

Other (OTH) AF: 0.317 AC: 670 AN: 2114

Alfa AF: 0.313 Hom.: 2204

Bravo AF: 0.297

TwinsUK AF: 0.318 AC: 1179

ALSPAC AF: 0.328 AC: 1264

ESP6500AA AF: 0.126 AC: 396

ESP6500EA AF: 0.243 AC: 1601

ExAC AF: 0.295 AC: 22211

Asia WGS AF: 0.596 AC: 2061 AN: 3466

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (5)
-	-	2	Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1;C4551884:Choroidal dystrophy, central areolar, 1;C5231408:Night blindness, congenital stationary, type1i (2)
-	-	1	Cone-rod dystrophy 6 (1)
-	-	1	Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1 (1)
-	-	1	GUCY2D-related recessive retinopathy (1)
1	-	-	Leber congenital amaurosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	2.0
DANN	Benign	0.86
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0000021	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.51
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.13
Sift	Benign	0.20	T
Sift4G	Benign	0.28	T
Polyphen		0.17	B
Vest4		0.040
MPC		1.2
ClinPred		0.0024	T
GERP RS		0.19
Varity_R		0.052
gMVP		0.30
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61749665; hg19: chr17-7906519; COSMIC: COSV54695038;