2-231732999-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_002601.4(PDE6D):​c.406G>A​(p.Asp136Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000297 in 1,611,924 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 (★). Synonymous variant affecting the same amino acid position (i.e. D136D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 2 hom. )

Consequence

PDE6D
NM_002601.4 missense

Scores

2
3
14

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 5.64
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.011261791).
BP6
Variant 2-231732999-C-T is Benign according to our data. Variant chr2-231732999-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 772599.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00165 (251/152236) while in subpopulation AFR AF= 0.0058 (241/41534). AF 95% confidence interval is 0.0052. There are 0 homozygotes in gnomad4. There are 128 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
PDE6DNM_002601.4 linkc.406G>A p.Asp136Asn missense_variant Exon 5 of 5 ENST00000287600.9 NP_002592.1 O43924Q6IB24
PDE6DXM_047444726.1 linkc.448G>A p.Asp150Asn missense_variant Exon 5 of 5 XP_047300682.1
PDE6DNM_001291018.2 linkc.*18G>A 3_prime_UTR_variant Exon 4 of 4 NP_001277947.1 O43924B8ZZK5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PDE6DENST00000287600.9 linkc.406G>A p.Asp136Asn missense_variant Exon 5 of 5 1 NM_002601.4 ENSP00000287600.4 O43924
PDE6DENST00000409772 linkc.*18G>A 3_prime_UTR_variant Exon 4 of 4 3 ENSP00000387108.1 B8ZZK5

Frequencies

GnomAD3 genomes
AF:
0.00165
AC:
251
AN:
152118
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00582
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000958
GnomAD3 exomes
AF:
0.000393
AC:
98
AN:
249078
Hom.:
0
AF XY:
0.000230
AC XY:
31
AN XY:
134818
show subpopulations
Gnomad AFR exome
AF:
0.00523
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000179
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000156
AC:
228
AN:
1459688
Hom.:
2
Cov.:
28
AF XY:
0.000103
AC XY:
75
AN XY:
726336
show subpopulations
Gnomad4 AFR exome
AF:
0.00535
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000991
Gnomad4 OTH exome
AF:
0.000348
GnomAD4 genome
AF:
0.00165
AC:
251
AN:
152236
Hom.:
0
Cov.:
32
AF XY:
0.00172
AC XY:
128
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.00580
Gnomad4 AMR
AF:
0.000458
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000948
Alfa
AF:
0.000283
Hom.:
0
Bravo
AF:
0.00168
ESP6500AA
AF:
0.00363
AC:
16
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000486
AC:
59

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

PDE6D-related disorder Benign:1
Feb 03, 2022
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Joubert syndrome 22 Benign:1
Jan 20, 2025
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
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.10
T
Eigen
Benign
0.021
Eigen_PC
Benign
0.19
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.95
D
M_CAP
Benign
0.0044
T
MetaRNN
Benign
0.011
T
MetaSVM
Benign
-0.84
T
MutationAssessor
Uncertain
2.0
M
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-0.36
N
REVEL
Benign
0.076
Sift
Benign
0.33
T
Sift4G
Benign
0.41
T
Polyphen
0.0040
B
Vest4
0.30
MVP
0.48
MPC
0.99
ClinPred
0.041
T
GERP RS
5.0
Varity_R
0.50
gMVP
0.48

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.15
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs142298615; hg19: chr2-232597709; API