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

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. T460T) has been classified as Likely 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

Publications

14 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
PDE6C-related retinopathy
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 -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 VariationId is 259942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006204.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6C	NM_006204.4	MANE Select	c.1380C>G	p.Thr460Thr	synonymous	Exon 10 of 22	NP_006195.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6C	ENST00000371447.4	TSL:1 MANE Select	c.1380C>G	p.Thr460Thr	synonymous	Exon 10 of 22	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

GnomAD2 exomes

AF:

0.274

AC:

68874

AN:

251304

AF XY:

0.270

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 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

African (AFR)

AF:

0.123

AC:

4108

AN:

33462

American (AMR)

AF:

0.359

AC:

16057

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.299

AC:

7810

AN:

26122

East Asian (EAS)

AF:

0.353

AC:

14000

AN:

39668

South Asian (SAS)

AF:

0.182

AC:

15727

AN:

86226

European-Finnish (FIN)

AF:

0.275

AC:

14693

AN:

53394

Middle Eastern (MID)

AF:

0.251

AC:

1448

AN:

5764

European-Non Finnish (NFE)

AF:

0.275

AC:

305950

AN:

1110548

Other (OTH)

AF:

0.268

AC:

16198

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

14199

28398

42596

56795

70994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10202

20404

30606

40808

51010

<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:

0.240

AC:

36490

AN:

152076

Hom.:

4801

Cov.:

AF XY:

0.240

AC XY:

17801

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.133

AC:

5506

AN:

41512

American (AMR)

AF:

0.309

AC:

4720

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.298

AC:

1033

AN:

3472

East Asian (EAS)

AF:

0.359

AC:

1850

AN:

5154

South Asian (SAS)

AF:

0.184

AC:

884

AN:

4814

European-Finnish (FIN)

AF:

0.277

AC:

2927

AN:

10560

Middle Eastern (MID)

AF:

0.269

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.276

AC:

18766

AN:

67988

Other (OTH)

AF:

0.252

AC:

530

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1370

2739

4109

5478

6848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

378

756

1134

1512

1890

<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:

0.232

Hom.:

1469

Bravo

AF:

0.243

Asia WGS

AF:

0.264

AC:

916

AN:

3478

EpiCase

AF:

0.284

EpiControl

AF:

0.288

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Achromatopsia (1)

Cone dystrophy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

6.6

(source)

DANN

Benign

0.67

PhyloP100

0.67

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over