rs12449814

Variant names:

• chr17-8008391-G-T
• rs12449814
• NM_000180.4:c.1668+359G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000180.4(GUCY2D):​c.1668+359G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 152,258 control chromosomes in the GnomAD database, including 200 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.040 (200 hom., cov: 32)
• Consequence: GUCY2D NM_000180.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2D	NM_000180.4	c.1668+359G>T		intron_variant	Intron 7 of 19	ENST00000254854.5	NP_000171.1
GUCY2D	XM_011523816.2	c.1668+359G>T		intron_variant	Intron 6 of 18		XP_011522118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5	c.1668+359G>T		intron_variant	Intron 7 of 19	1	NM_000180.4	ENSP00000254854.4

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6022 AN: 152140 Hom.: 198 Cov.: 32

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0516

Gnomad EAS AF: 0.0466

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.0541

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0371

Gnomad OTH AF: 0.0411

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0396 AC: 6036 AN: 152258 Hom.: 200 Cov.: 32 AF XY: 0.0402 AC XY: 2995 AN XY: 74460

African (AFR) AF: 0.0176 AC: 732 AN: 41526

American (AMR) AF: 0.103 AC: 1575 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0516 AC: 179 AN: 3470

East Asian (EAS) AF: 0.0467 AC: 242 AN: 5184

South Asian (SAS) AF: 0.0240 AC: 116 AN: 4826

European-Finnish (FIN) AF: 0.0541 AC: 574 AN: 10618

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0371 AC: 2523 AN: 68016

Other (OTH) AF: 0.0406 AC: 86 AN: 2116

Alfa AF: 0.0401 Hom.: 187

Bravo AF: 0.0459

Asia WGS AF: 0.0390 AC: 135 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.41
DANN	Benign	0.75
PhyloP100		-1.4
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: rs12449814; hg19: chr17-7911709;