NM_002601.4:c.402T>G

Variant names:

• chr2-231733003-A-C
• rs1414752195
• NM_002601.4:c.402T>G

Variant summary

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

The NM_002601.4(PDE6D):​c.402T>G​(p.Phe134Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,706 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F134F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PDE6D NM_002601.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.55
• Publications: 0 publications found

Genes affected

PDE6D (HGNC:8788): (phosphodiesterase 6D) This gene encodes the delta subunit of rod-specific photoreceptor phosphodiesterase (PDE), a key enzyme in the phototransduction cascade. A similar protein in cow functions in solubilizing membrane-bound PDE. In addition to its role in the PDE complex, the encoded protein is thought to bind to prenyl groups of proteins to target them to subcellular organelles called cilia. Mutations in this gene are associated with Joubert syndrome-22. Alternative splicing results in multiple splice variants. [provided by RefSeq, Mar 2014]

PDE6D Gene-Disease associations (from GenCC):

• Joubert syndrome 22

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• orofaciodigital syndrome type 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002601.4. 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
	PDE6D	NM_002601.4	MANE Select	c.402T>G	p.Phe134Leu	missense	Exon 5 of 5	NP_002592.1	O43924
	PDE6D	NM_001291018.2		c.*14T>G		3_prime_UTR	Exon 4 of 4	NP_001277947.1	B8ZZK5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6D	ENST00000287600.9	TSL:1 MANE Select	c.402T>G	p.Phe134Leu	missense	Exon 5 of 5	ENSP00000287600.4	O43924
	PDE6D	ENST00000938376.1		c.276T>G	p.Phe92Leu	missense	Exon 4 of 4	ENSP00000608435.1
	PDE6D	ENST00000409772.5	TSL:3	c.*14T>G		3_prime_UTR	Exon 4 of 4	ENSP00000387108.1	B8ZZK5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249148 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459706 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 726396

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.0000224 AC: 1 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110062

Other (OTH) AF: 0.00 AC: 0 AN: 60322

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.066
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.49
Sift	Benign	0.17	T
Sift4G	Benign	0.16	T
Polyphen		0.0090	B
Vest4		0.48
MutPred		0.83		Gain of sheet (P = 0.0477)
MVP		0.36
MPC		1.2
ClinPred		0.39	T
GERP RS		3.9
Varity_R		0.46
gMVP		0.89
Mutation Taster		=50/50

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: rs1414752195; hg19: chr2-232597713;