rs1409332

Positions:

• chr10-93646057-C-A
• chr10-93646057-C-G

Variant summary

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

The NM_006204.4(PDE6C):​c.1935+10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 1,479,756 control chromosomes in the GnomAD database, including 158,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14718 hom., cov: 32)
  • Exomes 𝑓: 0.46 (144151 hom.)
• Consequence: PDE6C NM_006204.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.15

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=-0.82).
• BP6: Variant 10-93646057-C-A is Benign according to our data. Variant chr10-93646057-C-A is described in ClinVar as [Benign]. Clinvar id is 259943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-93646057-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6C	NM_006204.4	c.1935+10C>A		intron_variant		ENST00000371447.4	NP_006195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE6C	ENST00000371447.4	c.1935+10C>A		intron_variant		1	NM_006204.4	ENSP00000360502.3

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65920 AN: 151872 Hom.: 14714 Cov.: 32

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.414

GnomAD3 exomes AF: 0.457 AC: 114263 AN: 250124 Hom.: 26645 AF XY: 0.462 AC XY: 62484 AN XY: 135146

Gnomad AFR exome AF: 0.315

Gnomad AMR exome AF: 0.404

Gnomad ASJ exome AF: 0.446

Gnomad EAS exome AF: 0.406

Gnomad SAS exome AF: 0.476

Gnomad FIN exome AF: 0.537

Gnomad NFE exome AF: 0.482

Gnomad OTH exome AF: 0.460

GnomAD4 exome AF: 0.464 AC: 615798 AN: 1327766 Hom.: 144151 Cov.: 20 AF XY: 0.467 AC XY: 311767 AN XY: 667986

Gnomad4 AFR exome AF: 0.309

Gnomad4 AMR exome AF: 0.404

Gnomad4 ASJ exome AF: 0.442

Gnomad4 EAS exome AF: 0.430

Gnomad4 SAS exome AF: 0.473

Gnomad4 FIN exome AF: 0.538

Gnomad4 NFE exome AF: 0.469

Gnomad4 OTH exome AF: 0.454

GnomAD4 genome AF: 0.434 AC: 65939 AN: 151990 Hom.: 14718 Cov.: 32 AF XY: 0.437 AC XY: 32434 AN XY: 74264

Gnomad4 AFR AF: 0.321

Gnomad4 AMR AF: 0.425

Gnomad4 ASJ AF: 0.444

Gnomad4 EAS AF: 0.409

Gnomad4 SAS AF: 0.473

Gnomad4 FIN AF: 0.554

Gnomad4 NFE AF: 0.484

Gnomad4 OTH AF: 0.417

Alfa AF: 0.465 Hom.: 10675

Bravo AF: 0.416

Asia WGS AF: 0.456 AC: 1587 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Cone dystrophy 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -

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	-0.82
CADD	Benign	1.7
DANN	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs1409332; hg19: chr10-95405814; COSMIC: COSV65116662;