rs7406106

Variant names:

• chr17-8002739-A-G
• rs7406106
• NM_000180.4:c.-10+5A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-8002739-A-G
• chr17-8002739-A-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.-10+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 345,844 control chromosomes in the GnomAD database, including 172,917 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (76127 hom., cov: 32)
  • Exomes 𝑓: 1.0 (96790 hom.)
• Consequence: GUCY2D NM_000180.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005104
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.16
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 17-8002739-A-G is Benign according to our data. Variant chr17-8002739-A-G is described in ClinVar as [Benign]. Clinvar id is 1258982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2D	NM_000180.4	c.-10+5A>G		splice_region_variant, intron_variant	Intron 1 of 19	ENST00000254854.5	NP_000171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5	c.-10+5A>G		splice_region_variant, intron_variant	Intron 1 of 19	1	NM_000180.4	ENSP00000254854.4

Frequencies

GnomAD3 genomes AF: 1.00 AC: 152139 AN: 152140 Hom.: 76069 Cov.: 32

Gnomad AFR AF: 1.00

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD4 exome AF: 1.00 AC: 193584 AN: 193588 Hom.: 96790 Cov.: 0 AF XY: 1.00 AC XY: 99827 AN XY: 99828

African (AFR) AF: 1.00 AC: 5226 AN: 5226

American (AMR) AF: 1.00 AC: 4800 AN: 4800

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 7176 AN: 7176

East Asian (EAS) AF: 1.00 AC: 14796 AN: 14796

South Asian (SAS) AF: 1.00 AC: 10664 AN: 10664

European-Finnish (FIN) AF: 1.00 AC: 14374 AN: 14374

Middle Eastern (MID) AF: 1.00 AC: 1010 AN: 1010

European-Non Finnish (NFE) AF: 1.00 AC: 122950 AN: 122954

Other (OTH) AF: 1.00 AC: 12588 AN: 12588

GnomAD4 genome AF: 1.00 AC: 152255 AN: 152256 Hom.: 76127 Cov.: 32 AF XY: 1.00 AC XY: 74426 AN XY: 74426

African (AFR) AF: 1.00 AC: 41574 AN: 41574

American (AMR) AF: 1.00 AC: 15309 AN: 15310

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5114 AN: 5114

South Asian (SAS) AF: 1.00 AC: 4830 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10626 AN: 10626

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68010 AN: 68010

Other (OTH) AF: 1.00 AC: 2116 AN: 2116

Alfa AF: 1.00 Hom.: 11572

Bravo AF: 1.00

Asia WGS AF: 1.00 AC: 3478 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.76
PhyloP100		1.2
PromoterAI		0.18	Neutral
Mutation Taster		=31/69	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
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: rs7406106; hg19: chr17-7906057;