rs616522

Positions:

• chr10-93635490-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000371447.4(PDE6C):​c.1270-7A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.748 in 1,605,934 control chromosomes in the GnomAD database, including 450,883 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41020 hom., cov: 32)
  • Exomes 𝑓: 0.75 (409863 hom.)
• Consequence: PDE6C ENST00000371447.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001724
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0270

Genes affected

PDE6C (HGNC:8787): (phosphodiesterase 6C) This gene encodes the alpha-prime subunit of cone phosphodiesterase, which is composed of a homodimer of two alpha-prime subunits and 3 smaller proteins of 11, 13, and 15 kDa. Mutations in this gene are associated with cone dystrophy type 4 (COD4). [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-93635490-A-G is Benign according to our data. Variant chr10-93635490-A-G is described in ClinVar as [Benign]. Clinvar id is 259940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-93635490-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6C	NM_006204.4	c.1270-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000371447.4	NP_006195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE6C	ENST00000371447.4	c.1270-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006204.4	ENSP00000360502	P1

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111462 AN: 151890 Hom.: 40982 Cov.: 32

Gnomad AFR AF: 0.714

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.739

Gnomad EAS AF: 0.650

Gnomad SAS AF: 0.827

Gnomad FIN AF: 0.728

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.743

GnomAD3 exomes AF: 0.733 AC: 184050 AN: 251112 Hom.: 68016 AF XY: 0.741 AC XY: 100634 AN XY: 135752

Gnomad AFR exome AF: 0.706

Gnomad AMR exome AF: 0.643

Gnomad ASJ exome AF: 0.730

Gnomad EAS exome AF: 0.659

Gnomad SAS exome AF: 0.832

Gnomad FIN exome AF: 0.727

Gnomad NFE exome AF: 0.749

Gnomad OTH exome AF: 0.767

GnomAD4 exome AF: 0.750 AC: 1089779 AN: 1453926 Hom.: 409863 Cov.: 31 AF XY: 0.752 AC XY: 544550 AN XY: 723928

Gnomad4 AFR exome AF: 0.720

Gnomad4 AMR exome AF: 0.651

Gnomad4 ASJ exome AF: 0.731

Gnomad4 EAS exome AF: 0.656

Gnomad4 SAS exome AF: 0.828

Gnomad4 FIN exome AF: 0.731

Gnomad4 NFE exome AF: 0.753

Gnomad4 OTH exome AF: 0.746

GnomAD4 genome AF: 0.734 AC: 111558 AN: 152008 Hom.: 41020 Cov.: 32 AF XY: 0.735 AC XY: 54635 AN XY: 74290

Gnomad4 AFR AF: 0.715

Gnomad4 AMR AF: 0.704

Gnomad4 ASJ AF: 0.739

Gnomad4 EAS AF: 0.650

Gnomad4 SAS AF: 0.827

Gnomad4 FIN AF: 0.728

Gnomad4 NFE AF: 0.752

Gnomad4 OTH AF: 0.742

Alfa AF: 0.749 Hom.: 94836

Bravo AF: 0.726

Asia WGS AF: 0.736 AC: 2558 AN: 3476

EpiCase AF: 0.747

EpiControl AF: 0.745

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cone dystrophy 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Achromatopsia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.4
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs616522; hg19: chr10-95395247; COSMIC: COSV65118225;