8-47774183-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006904.7(PRKDC):​c.12377C>T​(p.Pro4126Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PRKDC
NM_006904.7 missense

Scores

10
5
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60
Variant links:
Genes affected
PRKDC (HGNC:9413): (protein kinase, DNA-activated, catalytic subunit) This gene encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PK). It functions with the Ku70/Ku80 heterodimer protein in DNA double strand break repair and recombination. The protein encoded is a member of the PI3/PI4-kinase family.[provided by RefSeq, Jul 2010]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRKDCNM_006904.7 linkc.12377C>T p.Pro4126Leu missense_variant Exon 86 of 86 ENST00000314191.7 NP_008835.5 P78527-1
PRKDCNM_001081640.2 linkc.12284C>T p.Pro4095Leu missense_variant Exon 85 of 85 NP_001075109.1 P78527-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRKDCENST00000314191.7 linkc.12377C>T p.Pro4126Leu missense_variant Exon 86 of 86 1 NM_006904.7 ENSP00000313420.3 P78527-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 23, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.P4126L variant (also known as c.12377C>T), located in coding exon 86 of the PRKDC gene, results from a C to T substitution at nucleotide position 12377. The proline at codon 4126 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.69
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.63
D;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.97
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.057
D
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Pathogenic
3.2
M;.
PrimateAI
Uncertain
0.51
T
REVEL
Pathogenic
0.84
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
D;.
Vest4
0.70
MutPred
0.80
Gain of MoRF binding (P = 0.0309);.;
MVP
0.89
MPC
0.66
ClinPred
0.99
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.79
gMVP
0.95

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-48686744; API