5-149934000-T-C

Variant names:

Variant summary

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

The NM_000440.3(PDE6A):c.647A>G(p.Asn216Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00717 in 1,609,690 control chromosomes in the GnomAD database, including 695 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 348 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 347 hom. )

Consequence

PDE6A
NM_000440.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.83

Publications

7 publications found

Variant links:

Genes affected

PDE6A (HGNC:8785): (phosphodiesterase 6A) This gene encodes the cyclic-GMP (cGMP)-specific phosphodiesterase 6A alpha subunit, expressed in cells of the retinal rod outer segment. The phosphodiesterase 6 holoenzyme is a heterotrimer composed of an alpha, beta, and two gamma subunits. cGMP is an important regulator of rod cell membrane current, and its dynamic concentration is established by phosphodiesterase 6A cGMP hydrolysis and guanylate cyclase cGMP synthesis. The protein is a subunit of a key phototransduction enzyme and participates in processes of transmission and amplification of the visual signal. Mutations in this gene have been identified as one cause of autosomal recessive retinitis pigmentosa. [provided by RefSeq, Jul 2008]

PDE6A Gene-Disease associations (from GenCC):

inherited retinal dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
retinitis pigmentosa 43
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PDE6A 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=0.002271533).

BP6

Variant 5-149934000-T-C is Benign according to our data. Variant chr5-149934000-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 351997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000440.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6A	NM_000440.3	MANE Select	c.647A>G	p.Asn216Ser	missense	Exon 3 of 22	NP_000431.2
	PDE6A	NM_001410788.1		c.475-2832A>G		intron	N/A	NP_001397717.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PDE6A	ENST00000255266.10	TSL:1 MANE Select	c.647A>G	p.Asn216Ser	missense	Exon 3 of 22	ENSP00000255266.5
PDE6A	ENST00000508173.5	TSL:1	n.767A>G		non_coding_transcript_exon	Exon 3 of 20
PDE6A	ENST00000613228.1	TSL:5	c.475-2832A>G		intron	N/A	ENSP00000478060.1

Frequencies

GnomAD3 genomes

AF:

0.0373

AC:

5674

AN:

152188

Hom.:

345

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.0291

GnomAD2 exomes

AF:

0.0101

AC:

2528

AN:

250826

AF XY:

0.00771

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.00559

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00402

AC:

5852

AN:

1457384

Hom.:

347

Cov.:

AF XY:

0.00351

AC XY:

2546

AN XY:

725424

show subpopulations

African (AFR)

AF:

0.136

AC:

4523

AN:

33330

American (AMR)

AF:

0.00602

AC:

269

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

268

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.000244

AC:

AN:

86082

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00330

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000187

AC:

207

AN:

1108110

Other (OTH)

AF:

0.00903

AC:

544

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

240

480

719

959

1199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

272

408

544

680

<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:

0.0374

AC:

5692

AN:

152306

Hom.:

348

Cov.:

AF XY:

0.0362

AC XY:

2695

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.130

AC:

5395

AN:

41548

American (AMR)

AF:

0.0108

AC:

165

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68024

Other (OTH)

AF:

0.0288

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

249

497

746

994

1243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0188

Hom.:

280

Bravo

AF:

0.0428

ESP6500AA

AF:

0.121

AC:

535

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.0121

AC:

1470

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000297

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Benign

-0.059

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

4.8

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.1

REVEL

Benign

0.11

Sift

Benign

0.23

Sift4G

Benign

0.60

Polyphen

0.080

Vest4

0.084

MPC

0.092

ClinPred

0.038

GERP RS

5.4

Varity_R

0.29

gMVP

0.24

Mutation Taster

=85/15

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

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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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over