rs148661165

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006204.4(PDE6C):c.2501A>G(p.Glu834Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,613,582 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 14 hom. )

Consequence

PDE6C
NM_006204.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 8.53

Publications

9 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009043366).

BP6

Variant 10-93663161-A-G is Benign according to our data. Variant chr10-93663161-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259945.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00219 (333/152248) while in subpopulation EAS AF = 0.00425 (22/5172). AF 95% confidence interval is 0.00288. There are 0 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 14 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE6C	NM_006204.4 link	c.2501A>G	p.Glu834Gly	missense_variant	Exon 21 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.2501A>G	p.Glu834Gly	missense_variant	Exon 21 of 22	1	NM_006204.4	ENSP00000360502.3		P51160
PDE6C	ENST00000475427.2 link	n.162+518A>G		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

331

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00424

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00234

AC:

585

AN:

250486

AF XY:

0.00245

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.00240

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.00233

Gnomad OTH exome

AF:

0.00263

GnomAD4 exome

AF:

0.00247

AC:

3607

AN:

1461334

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

1829

AN XY:

726942

show subpopulations

African (AFR)

AF:

0.00129

AC:

AN:

33444

American (AMR)

AF:

0.00139

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

295

AN:

26116

East Asian (EAS)

AF:

0.000807

AC:

AN:

39632

South Asian (SAS)

AF:

0.00224

AC:

193

AN:

86230

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00244

AC:

2713

AN:

1111730

Other (OTH)

AF:

0.00409

AC:

247

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

185

370

555

740

925

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<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:

0.00219

AC:

333

AN:

152248

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41548

American (AMR)

AF:

0.00203

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3470

East Asian (EAS)

AF:

0.00425

AC:

AN:

5172

South Asian (SAS)

AF:

0.00104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00240

AC:

163

AN:

68008

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00257

Hom.:

Bravo

AF:

0.00228

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00213

AC:

259

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00300

EpiControl

AF:

0.00309

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PDE6C: BP4, BS2 -

Achromatopsia

Uncertain:1

May 01, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cone dystrophy 4

Uncertain:1

May 01, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.49

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.0090

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.5

PhyloP100

8.5

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.35

Sift

Uncertain

0.027

Sift4G

Uncertain

0.041

Polyphen

0.97

Vest4

0.55

MVP

0.81

MPC

0.40

ClinPred

0.033

GERP RS

4.9

Varity_R

0.19

gMVP

0.53

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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