Genetic Variant PDE6A:p.Asn216Thr (chr5-149934000-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000440.3(PDE6A):c.647A>C(p.Asn216Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,438 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N216S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PDE6A
NM_000440.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE6A	NM_000440.3 link	c.647A>C	p.Asn216Thr	missense_variant	Exon 3 of 22	ENST00000255266.10	NP_000431.2	P16499
PDE6A	NM_001410788.1 link	c.475-2832A>C		intron_variant	Intron 1 of 19		NP_001397717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PDE6A	ENST00000255266.10 link	c.647A>C	p.Asn216Thr	missense_variant	Exon 3 of 22	1	NM_000440.3	ENSP00000255266.5	P16499
PDE6A	ENST00000508173.5 link	n.767A>C		non_coding_transcript_exon_variant	Exon 3 of 20	1
PDE6A	ENST00000613228.1 link	c.475-2832A>C		intron_variant	Intron 1 of 19	5		ENSP00000478060.1	F1T0K3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457438

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725452

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33380

American (AMR)

AF:

0.00

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108112

Other (OTH)

AF:

0.00

AC:

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

280

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

Eigen

Benign

-0.088

Eigen_PC

Benign

0.092

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.78

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.66

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.5

PhyloP100

4.8

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.0

REVEL

Benign

0.12

Sift

Benign

0.79

Sift4G

Benign

0.69

Polyphen

0.17

Vest4

0.57

MutPred

0.47

Loss of stability (P = 0.1223);

MVP

0.83

MPC

0.25

ClinPred

0.83

GERP RS

5.4

Varity_R

0.36

gMVP

0.28

Mutation Taster

=54/46

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over