rs701865

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006204.4(PDE6C):c.808T>A(p.Ser270Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,612,712 control chromosomes in the GnomAD database, including 109,342 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S270A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.39 ( 11989 hom., cov: 32)

Exomes 𝑓: 0.36 ( 97353 hom. )

Consequence

PDE6C
NM_006204.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.18

Publications

36 publications found

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 Gene-Disease associations (from GenCC):

cone dystrophy 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
inherited retinal dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
cone dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
achromatopsia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PDE6C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.941855E-4).

BP6

Variant 10-93622016-T-A is Benign according to our data. Variant chr10-93622016-T-A is described in ClinVar as Benign. ClinVar VariationId is 259947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE6C	NM_006204.4 link	c.808T>A	p.Ser270Thr	missense_variant	Exon 4 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.808T>A	p.Ser270Thr	missense_variant	Exon 4 of 22	1	NM_006204.4	ENSP00000360502.3		P51160

Frequencies

GnomAD3 genomes

AF:

0.393

AC:

59675

AN:

151866

Hom.:

11968

Cov.:

show subpopulations

Gnomad AFR

AF:

0.462

Gnomad AMI

AF:

0.432

Gnomad AMR

AF:

0.420

Gnomad ASJ

AF:

0.337

Gnomad EAS

AF:

0.478

Gnomad SAS

AF:

0.318

Gnomad FIN

AF:

0.329

Gnomad MID

AF:

0.353

Gnomad NFE

AF:

0.357

Gnomad OTH

AF:

0.379

GnomAD2 exomes

AF:

0.376

AC:

94516

AN:

251358

AF XY:

0.369

show subpopulations

Gnomad AFR exome

AF:

0.468

Gnomad AMR exome

AF:

0.438

Gnomad ASJ exome

AF:

0.346

Gnomad EAS exome

AF:

0.473

Gnomad FIN exome

AF:

0.335

Gnomad NFE exome

AF:

0.356

Gnomad OTH exome

AF:

0.352

GnomAD4 exome

AF:

0.362

AC:

529034

AN:

1460726

Hom.:

97353

Cov.:

AF XY:

0.361

AC XY:

262270

AN XY:

726714

show subpopulations

African (AFR)

AF:

0.464

AC:

15526

AN:

33458

American (AMR)

AF:

0.435

AC:

19468

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.342

AC:

8933

AN:

26130

East Asian (EAS)

AF:

0.479

AC:

19022

AN:

39682

South Asian (SAS)

AF:

0.321

AC:

27709

AN:

86236

European-Finnish (FIN)

AF:

0.335

AC:

17852

AN:

53350

Middle Eastern (MID)

AF:

0.367

AC:

2118

AN:

5766

European-Non Finnish (NFE)

AF:

0.356

AC:

395676

AN:

1111022

Other (OTH)

AF:

0.377

AC:

22730

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

17127

34253

51380

68506

85633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12758

25516

38274

51032

63790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.393

AC:

59741

AN:

151986

Hom.:

11989

Cov.:

AF XY:

0.390

AC XY:

28986

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.462

AC:

19149

AN:

41406

American (AMR)

AF:

0.420

AC:

6419

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.337

AC:

1170

AN:

3468

East Asian (EAS)

AF:

0.478

AC:

2474

AN:

5176

South Asian (SAS)

AF:

0.316

AC:

1519

AN:

4808

European-Finnish (FIN)

AF:

0.329

AC:

3478

AN:

10574

Middle Eastern (MID)

AF:

0.366

AC:

106

AN:

290

European-Non Finnish (NFE)

AF:

0.357

AC:

24230

AN:

67964

Other (OTH)

AF:

0.382

AC:

803

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1839

3678

5517

7356

9195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

570

1140

1710

2280

2850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.345

Hom.:

6946

Bravo

AF:

0.408

TwinsUK

AF:

0.375

AC:

1390

ALSPAC

AF:

0.362

AC:

1397

ESP6500AA

AF:

0.463

AC:

2039

ESP6500EA

AF:

0.355

AC:

3050

ExAC

AF:

0.373

AC:

45271

Asia WGS

AF:

0.417

AC:

1449

AN:

3478

EpiCase

AF:

0.363

EpiControl

AF:

0.366

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

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

This variant is associated with the following publications: (PMID: 22449891) -

Cone dystrophy 4

Benign:2

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. -

May 28, 2019

Mendelics

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.2

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.076

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.23

MetaRNN

Benign

0.00069

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.1

PhyloP100

2.2

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.030

REVEL

Benign

0.092

Sift

Benign

0.45

Sift4G

Benign

0.53

Polyphen

0.0

Vest4

0.014

MPC

0.23

ClinPred

0.0040

GERP RS

4.8

Varity_R

0.036

gMVP

0.15

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over