NM_000440.3:c.*2542G>A

Variant names:

• chr5-149858353-C-T
• rs30884
• NM_000440.3:c.*2542G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000440.3(PDE6A):​c.*2542G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 152,068 control chromosomes in the GnomAD database, including 11,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (11159 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PDE6A NM_000440.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.204
• Publications: 11 publications found

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):

• PDE6A-related retinopathy

  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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 5-149858353-C-T is Benign according to our data. Variant chr5-149858353-C-T is described in ClinVar as Benign. ClinVar VariationId is 351943.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.424 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6A	NM_000440.3	MANE Select	c.*2542G>A		3_prime_UTR	Exon 22 of 22	NP_000431.2	P16499
	PDE6A	NM_001410788.1		c.*2542G>A		3_prime_UTR	Exon 20 of 20	NP_001397717.1	F1T0K3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6A	ENST00000255266.10	TSL:1 MANE Select	c.*2542G>A		3_prime_UTR	Exon 22 of 22	ENSP00000255266.5	P16499
	PDE6A	ENST00000508173.5	TSL:1	n.5309G>A		non_coding_transcript_exon	Exon 20 of 20
	PDE6A	ENST00000613228.1	TSL:5	c.*2542G>A		3_prime_UTR	Exon 20 of 20	ENSP00000478060.1	F1T0K3

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56775 AN: 151950 Hom.: 11143 Cov.: 32

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.374

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.374 AC: 56838 AN: 152068 Hom.: 11159 Cov.: 32 AF XY: 0.374 AC XY: 27789 AN XY: 74324

African (AFR) AF: 0.263 AC: 10904 AN: 41490

American (AMR) AF: 0.433 AC: 6615 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 1123 AN: 3470

East Asian (EAS) AF: 0.377 AC: 1951 AN: 5178

South Asian (SAS) AF: 0.251 AC: 1213 AN: 4824

European-Finnish (FIN) AF: 0.445 AC: 4690 AN: 10550

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29114 AN: 67968

Other (OTH) AF: 0.377 AC: 796 AN: 2110

Alfa AF: 0.407 Hom.: 39973

Bravo AF: 0.368

Asia WGS AF: 0.326 AC: 1131 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.59
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs30884; hg19: chr5-149237916;