5-149934000-T-G

Position:

• chr5-149934000-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

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. 12/21 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 Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PDE6A NM_000440.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.83

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain GAF 1 (size 149) in uniprot entity PDE6A_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000440.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-149934000-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6A	NM_000440.3	c.647A>C	p.Asn216Thr	missense_variant	3/22	ENST00000255266.10	NP_000431.2
PDE6A	NM_001410788.1	c.475-2832A>C		intron_variant			NP_001397717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE6A	ENST00000255266.10	c.647A>C	p.Asn216Thr	missense_variant	3/22	1	NM_000440.3	ENSP00000255266	P1
PDE6A	ENST00000508173.5	n.767A>C		non_coding_transcript_exon_variant	3/20	1
PDE6A	ENST00000613228.1	c.475-2832A>C		intron_variant		5		ENSP00000478060

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457438 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725452

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.088
Eigen_PC	Benign	0.092
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.0027	P
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.12
Sift	Benign	0.79	T
Sift4G	Benign	0.69	T
Polyphen		0.17	B
Vest4		0.57
MutPred		0.47		Loss of stability (P = 0.1223);
MVP		0.83
MPC		0.25
ClinPred		0.83	D
GERP RS		5.4
Varity_R		0.36
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs10057110; hg19: chr5-149313563;