Genetic Variant PDE6C:p.Thr460Thr (chr10-93635607-C-G) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_006204.4(PDE6C):c.1380C>G(p.Thr460Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,612,322 control chromosomes in the GnomAD database, including 60,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4801 hom., cov: 32)

Exomes 𝑓: 0.27 ( 55377 hom. )

Consequence

PDE6C
NM_006204.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.665

Variant links:

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]

PDE6C links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 10-93635607-C-G is Benign according to our data. Variant chr10-93635607-C-G is described in ClinVar as [Benign]. Clinvar id is 259942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-93635607-C-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.665 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE6C	NM_006204.4 link	c.1380C>G	p.Thr460Thr	synonymous_variant	Exon 10 of 22	ENST00000371447.4	NP_006195.3	P51160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE6C	ENST00000371447.4 link	c.1380C>G	p.Thr460Thr	synonymous_variant	Exon 10 of 22	1	NM_006204.4	ENSP00000360502.3		P51160

Frequencies

GnomAD3 genomes

AF:

0.240

AC:

36479

AN:

151956

Hom.:

4800

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.214

Gnomad AMR

AF:

0.309

Gnomad ASJ

AF:

0.298

Gnomad EAS

AF:

0.359

Gnomad SAS

AF:

0.184

Gnomad FIN

AF:

0.277

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.276

Gnomad OTH

AF:

0.251

GnomAD3 exomes

AF:

0.274

AC:

68874

AN:

251304

Hom.:

10104

AF XY:

0.270

AC XY:

36651

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.367

Gnomad ASJ exome

AF:

0.302

Gnomad EAS exome

AF:

0.347

Gnomad SAS exome

AF:

0.179

Gnomad FIN exome

AF:

0.278

Gnomad NFE exome

AF:

0.278

Gnomad OTH exome

AF:

0.250

GnomAD4 exome

AF:

0.271

AC:

395991

AN:

1460246

Hom.:

55377

Cov.:

AF XY:

0.269

AC XY:

195470

AN XY:

726560

show subpopulations

Gnomad4 AFR exome

AF:

0.123

Gnomad4 AMR exome

AF:

0.359

Gnomad4 ASJ exome

AF:

0.299

Gnomad4 EAS exome

AF:

0.353

Gnomad4 SAS exome

AF:

0.182

Gnomad4 FIN exome

AF:

0.275

Gnomad4 NFE exome

AF:

0.275

Gnomad4 OTH exome

AF:

0.268

GnomAD4 genome

AF:

0.240

AC:

36490

AN:

152076

Hom.:

4801

Cov.:

AF XY:

0.240

AC XY:

17801

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.133

Gnomad4 AMR

AF:

0.309

Gnomad4 ASJ

AF:

0.298

Gnomad4 EAS

AF:

0.359

Gnomad4 SAS

AF:

0.184

Gnomad4 FIN

AF:

0.277

Gnomad4 NFE

AF:

0.276

Gnomad4 OTH

AF:

0.252

Alfa

AF:

0.232

Hom.:

1469

Bravo

AF:

0.243

Asia WGS

AF:

0.264

AC:

916

AN:

3478

EpiCase

AF:

0.284

EpiControl

AF:

0.288

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Achromatopsia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cone dystrophy 4

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

-0.36

CADD

Benign

6.6

DANN

Benign

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over