rs112372281

Variant names:

• chr17-8014859-G-T
• rs112372281
• NM_000180.4:c.2577G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-8014859-G-T
• chr17-8014859-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 NM_000180.4(GUCY2D):c.2577G>T (p.Pro859=) variant is located at the first base of exon 14 and does not alter the amino acid (proline) at position p.859. The splicing impact predictor SpliceAI gives a delta score of 0.03, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.04139, with 3871 alleles / 91074 total alleles in the South 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 141 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). 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. (VCEP specifications version 1.0.0; date of approval 01/22/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA201118/MONDO:0100453/167

• Frequency:
  • Genomes: 𝑓 0.0059 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (127 hom.)
• Consequence: GUCY2D NM_000180.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.7349
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 0.332
• 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

Specifications for GUCY2D are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.2577G>T	p.Pro859Pro	splice_region synonymous	Exon 14 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.2577G>T	p.Pro859Pro	splice_region synonymous	Exon 14 of 20	ENSP00000254854.4	Q02846
	ENSG00000279174	ENST00000623126.1	TSL:6	n.1520C>A		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000299408	ENST00000763246.1		n.147-142C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00581 AC: 884 AN: 152132 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0481

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00679 AC: 1707 AN: 251356 AF XY: 0.00834

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000634

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00360 AC: 5265 AN: 1461852 Hom.: 127 Cov.: 35 AF XY: 0.00470 AC XY: 3420 AN XY: 727228

African (AFR) AF: 0.0155 AC: 518 AN: 33476

American (AMR) AF: 0.00105 AC: 47 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00295 AC: 77 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0422 AC: 3637 AN: 86254

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5758

European-Non Finnish (NFE) AF: 0.000587 AC: 653 AN: 1111994

Other (OTH) AF: 0.00517 AC: 312 AN: 60394

GnomAD4 genome AF: 0.00587 AC: 893 AN: 152250 Hom.: 14 Cov.: 32 AF XY: 0.00629 AC XY: 468 AN XY: 74446

African (AFR) AF: 0.0140 AC: 583 AN: 41526

American (AMR) AF: 0.000980 AC: 15 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0485 AC: 234 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68018

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00247 Hom.: 9

Bravo AF: 0.00516

Asia WGS AF: 0.0310 AC: 109 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1 (1)
-	-	1	GUCY2D-related recessive retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.64
PhyloP100		0.33
Mutation Taster		=57/43	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.73
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.030		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: rs112372281; hg19: chr17-7918177;