2-231738020-G-A

Variant names:

• chr2-231738020-G-A
• rs151191604
• NM_002601.4:c.258C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002601.4(PDE6D):​c.258C>T​(p.Cys86Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000575 in 1,613,946 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (2 hom.)
• Consequence: PDE6D NM_002601.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.56

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 2-231738020-G-A is Benign according to our data. Variant chr2-231738020-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 772606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.56 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000309 (47/152320) while in subpopulation NFE AF= 0.000515 (35/68016). AF 95% confidence interval is 0.000379. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE6D	NM_002601.4	c.258C>T	p.Cys86Cys	synonymous_variant	Exon 3 of 5	ENST00000287600.9	NP_002592.1
PDE6D	NM_001291018.2	c.258C>T	p.Cys86Cys	synonymous_variant	Exon 3 of 4		NP_001277947.1
PDE6D	XM_047444726.1	c.300C>T	p.Cys100Cys	synonymous_variant	Exon 3 of 5		XP_047300682.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE6D	ENST00000287600.9	c.258C>T	p.Cys86Cys	synonymous_variant	Exon 3 of 5	1	NM_002601.4	ENSP00000287600.4
PDE6D	ENST00000428104.2	c.201C>T	p.Cys67Cys	synonymous_variant	Exon 4 of 5	3		ENSP00000399098.2
PDE6D	ENST00000409772.5	c.258C>T	p.Cys86Cys	synonymous_variant	Exon 3 of 4	3		ENSP00000387108.1
PDE6D	ENST00000486044.1	n.407C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000382 AC: 96 AN: 251178 Hom.: 1 AF XY: 0.000376 AC XY: 51 AN XY: 135758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000899

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000493

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000603 AC: 881 AN: 1461626 Hom.: 2 Cov.: 30 AF XY: 0.000582 AC XY: 423 AN XY: 727112

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000712

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74480

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000409 Hom.: 0

Bravo AF: 0.000325

EpiCase AF: 0.000763

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

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PDE6D: BP4, BP7 -

Joubert syndrome 22 Benign:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs151191604; hg19: chr2-232602730;