rs56348143

Variant names:

• chr17-8015920-G-T
• rs56348143
• NM_000180.4:c.3044-7G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-8015920-G-T
• chr17-8015920-G-A

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 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

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.3044-7G>T		splice_region intron	N/A	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.3044-7G>T		splice_region intron	N/A	ENSP00000254854.4	Q02846
	ENSG00000279174	ENST00000623126.1	TSL:6	n.459C>A		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000299408	ENST00000763246.1		n.146+12C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4269 AN: 152176 Hom.: 97 Cov.: 33

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

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.: 32 AF XY: 0.0378 AC XY: 27327 AN XY: 723614

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: 3 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

GnomAD4 genome AF: 0.0280 AC: 4265 AN: 152294 Hom.: 97 Cov.: 33 AF XY: 0.0269 AC XY: 2004 AN XY: 74458

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: 1 AN: 5172

South Asian (SAS) AF: 0.00538 AC: 26 AN: 4830

European-Finnish (FIN) AF: 0.0170 AC: 181 AN: 10624

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0444 AC: 3021 AN: 68004

Other (OTH) AF: 0.0326 AC: 69 AN: 2116

Alfa AF: 0.0312 Hom.: 37

Bravo AF: 0.0276

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1 (1)
-	-	1	GUCY2D-related recessive retinopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.7
DANN	Benign	0.86
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56348143; hg19: chr17-7919238;