17-8016436-C-T

Variant names:

• chr17-8016436-C-T
• rs79887212
• NM_000180.4:c.3225-7C>T

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.3225-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 1,556,222 control chromosomes in the GnomAD database, including 446 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (34 hom., cov: 33)
  • Exomes 𝑓: 0.021 (412 hom.)
• Consequence: GUCY2D NM_000180.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003757
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.126
• Publications: 1 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=-0.78).
• BP6: Variant 17-8016436-C-T is Benign according to our data. Variant chr17-8016436-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2D	NM_000180.4	c.3225-7C>T		splice_region_variant, intron_variant	Intron 18 of 19	ENST00000254854.5	NP_000171.1
GUCY2D	XM_011523816.2	c.3225-7C>T		splice_region_variant, intron_variant	Intron 17 of 18		XP_011522118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5	c.3225-7C>T		splice_region_variant, intron_variant	Intron 18 of 19	1	NM_000180.4	ENSP00000254854.4
GUCY2D	ENST00000574510.1	n.163-7C>T		splice_region_variant, intron_variant	Intron 1 of 1	4
ENSG00000279174	ENST00000623126.1	n.-58G>A		upstream_gene_variant		6
ENSG00000299408	ENST00000763246.1	n.-77G>A		upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2857 AN: 152158 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.0594

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0447

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0223

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0205 AC: 3399 AN: 166208 AF XY: 0.0202

Gnomad AFR exome AF: 0.00420

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.0603

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0462

Gnomad NFE exome AF: 0.0240

Gnomad OTH exome AF: 0.0320

GnomAD4 exome AF: 0.0206 AC: 28958 AN: 1403946 Hom.: 412 Cov.: 30 AF XY: 0.0205 AC XY: 14222 AN XY: 693826

African (AFR) AF: 0.00282 AC: 91 AN: 32282

American (AMR) AF: 0.0157 AC: 581 AN: 37000

Ashkenazi Jewish (ASJ) AF: 0.0569 AC: 1434 AN: 25220

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 37052

South Asian (SAS) AF: 0.00439 AC: 351 AN: 79962

European-Finnish (FIN) AF: 0.0444 AC: 2060 AN: 46436

Middle Eastern (MID) AF: 0.0576 AC: 327 AN: 5678

European-Non Finnish (NFE) AF: 0.0210 AC: 22753 AN: 1082060

Other (OTH) AF: 0.0233 AC: 1360 AN: 58256

GnomAD4 genome AF: 0.0188 AC: 2857 AN: 152276 Hom.: 34 Cov.: 33 AF XY: 0.0196 AC XY: 1462 AN XY: 74444

African (AFR) AF: 0.00419 AC: 174 AN: 41572

American (AMR) AF: 0.0235 AC: 360 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0594 AC: 206 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.0447 AC: 474 AN: 10612

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0223 AC: 1519 AN: 68024

Other (OTH) AF: 0.0303 AC: 64 AN: 2114

Alfa AF: 0.0200 Hom.: 17

Bravo AF: 0.0167

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 23, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Sep 03, 2014

Eurofins Ntd Llc (ga)

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.6
DANN	Benign	0.93
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0
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: rs79887212; hg19: chr17-7919754; COSMIC: COSV107293675; COSMIC: COSV107293675;