2-231732996-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002601.4(PDE6D):c.409G>A(p.Asp137Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,612,136 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (5 hom.)
• Consequence: PDE6D NM_002601.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.36

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010318369).
• BP6: Variant 2-231732996-C-T is Benign according to our data. Variant chr2-231732996-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 541700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00212 (323/152256) while in subpopulation AFR AF= 0.00657 (273/41564). AF 95% confidence interval is 0.00593. There are 3 homozygotes in gnomad4. There are 144 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE6D	NM_002601.4	c.409G>A	p.Asp137Asn	missense_variant	5/5	ENST00000287600.9
PDE6D	XM_047444726.1	c.451G>A	p.Asp151Asn	missense_variant	5/5
PDE6D	NM_001291018.2	c.*21G>A		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE6D	ENST00000287600.9	c.409G>A	p.Asp137Asn	missense_variant	5/5	1	NM_002601.4	P1
PDE6D	ENST00000409772.5	c.*21G>A		3_prime_UTR_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 319 AN: 152138 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000662 AC: 165 AN: 249158 Hom.: 0 AF XY: 0.000549 AC XY: 74 AN XY: 134868

Gnomad AFR exome AF: 0.00677

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000421

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00100 AC: 1462 AN: 1459880 Hom.: 5 Cov.: 28 AF XY: 0.000962 AC XY: 699 AN XY: 726458

Gnomad4 AFR exome AF: 0.00742

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.000630

GnomAD4 genome AF: 0.00212 AC: 323 AN: 152256 Hom.: 3 Cov.: 32 AF XY: 0.00193 AC XY: 144 AN XY: 74424

Gnomad4 AFR AF: 0.00657

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000898 Hom.: 0

Bravo AF: 0.00241

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000848 AC: 103

EpiCase AF: 0.000655

EpiControl AF: 0.000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

PDE6D: BS2 -

Joubert syndrome 22 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.042
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.12
Sift	Benign	0.22	T
Sift4G	Benign	0.36	T
Polyphen		0.022	B
Vest4		0.57
MVP		0.47
MPC		1.0
ClinPred		0.044	T
GERP RS		5.3
Varity_R		0.43
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs146510084; hg19: chr2-232597706; COSMIC: COSV99807692; COSMIC: COSV99807692;