NM_000180.4:c.3043+20G>C

Variant names:

• chr17-8015861-G-C
• rs78844078
• NM_000180.4:c.3043+20G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000180.4(GUCY2D):​c.3043+20G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,607,184 control chromosomes in the GnomAD database, including 560 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (55 hom., cov: 33)
  • Exomes 𝑓: 0.019 (505 hom.)
• Consequence: GUCY2D NM_000180.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.508
• Publications: 2 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

ENSG00000279174 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-8015861-G-C is Benign according to our data. Variant chr17-8015861-G-C is described in ClinVar as Benign. ClinVar VariationId is 255477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.06 is higher than 0.05.

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.3043+20G>C		intron	N/A	NP_000171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2D	ENST00000254854.5	TSL:1 MANE Select	c.3043+20G>C		intron	N/A	ENSP00000254854.4
	ENSG00000279174	ENST00000623126.1	TSL:6	n.518C>G		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000299408	ENST00000763246.1		n.146+71C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2627 AN: 152208 Hom.: 55 Cov.: 33

Gnomad AFR AF: 0.00444

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0391

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0309

Gnomad SAS AF: 0.0655

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0239 AC: 5729 AN: 239250 AF XY: 0.0257

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.0293

Gnomad ASJ exome AF: 0.00275

Gnomad EAS exome AF: 0.0263

Gnomad FIN exome AF: 0.0194

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0193 AC: 28077 AN: 1454858 Hom.: 505 Cov.: 31 AF XY: 0.0207 AC XY: 14951 AN XY: 723572

African (AFR) AF: 0.00279 AC: 93 AN: 33364

American (AMR) AF: 0.0301 AC: 1326 AN: 44090

Ashkenazi Jewish (ASJ) AF: 0.00227 AC: 59 AN: 26022

East Asian (EAS) AF: 0.0126 AC: 499 AN: 39474

South Asian (SAS) AF: 0.0671 AC: 5725 AN: 85328

European-Finnish (FIN) AF: 0.0189 AC: 995 AN: 52660

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5756

European-Non Finnish (NFE) AF: 0.0162 AC: 17938 AN: 1108020

Other (OTH) AF: 0.0223 AC: 1344 AN: 60144

GnomAD4 genome AF: 0.0173 AC: 2630 AN: 152326 Hom.: 55 Cov.: 33 AF XY: 0.0189 AC XY: 1404 AN XY: 74480

African (AFR) AF: 0.00442 AC: 184 AN: 41586

American (AMR) AF: 0.0393 AC: 601 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.0306 AC: 158 AN: 5170

South Asian (SAS) AF: 0.0660 AC: 319 AN: 4834

European-Finnish (FIN) AF: 0.0213 AC: 226 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0160 AC: 1085 AN: 68020

Other (OTH) AF: 0.0184 AC: 39 AN: 2114

Alfa AF: 0.00821 Hom.: 3

Bravo AF: 0.0148

Asia WGS AF: 0.0570 AC: 199 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 08, 2019

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.2
DANN	Benign	0.67
PhyloP100		0.51
Mutation Taster		=100/0	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: rs78844078; hg19: chr17-7919179;