2-231737247-G-T

Variant names:

• chr2-231737247-G-T
• NM_002601.4:c.311C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002601.4(PDE6D):​c.311C>A​(p.Thr104Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T104I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PDE6D NM_002601.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE6D	NM_002601.4	c.311C>A	p.Thr104Asn	missense_variant	Exon 4 of 5	ENST00000287600.9	NP_002592.1
PDE6D	XM_047444726.1	c.353C>A	p.Thr118Asn	missense_variant	Exon 4 of 5		XP_047300682.1
PDE6D	NM_001291018.2	c.265+766C>A		intron_variant	Intron 3 of 3		NP_001277947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE6D	ENST00000287600.9	c.311C>A	p.Thr104Asn	missense_variant	Exon 4 of 5	1	NM_002601.4	ENSP00000287600.4
PDE6D	ENST00000428104.2	c.254C>A	p.Thr85Asn	missense_variant	Exon 5 of 5	3		ENSP00000399098.2
PDE6D	ENST00000409772.5	c.265+766C>A		intron_variant	Intron 3 of 3	3		ENSP00000387108.1
PDE6D	ENST00000486044.1	n.*175C>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460970 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 726882

Gnomad4 AFR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.049	D;T
Sift4G	Uncertain	0.0050	D;.
Polyphen		0.96	D;.
Vest4		0.92
MutPred		0.93		Gain of disorder (P = 0.2652);.;
MVP		0.78
MPC		1.8
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-232601957;