chr8-47889068-G-A

Position:

chr8-47889068-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006904.7(PRKDC):c.4226C>T(p.Ser1409Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000421 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1409C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

PRKDC
NM_006904.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.39

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]

PRKDC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3275199).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7 linkuse as main transcript	c.4226C>T	p.Ser1409Phe	missense_variant	33/86	ENST00000314191.7
PRKDC	NM_001081640.2 linkuse as main transcript	c.4226C>T	p.Ser1409Phe	missense_variant	33/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7 linkuse as main transcript	c.4226C>T	p.Ser1409Phe	missense_variant	33/86	1	NM_006904.7	P1	P78527-1
PRKDC	ENST00000338368.7 linkuse as main transcript	c.4226C>T	p.Ser1409Phe	missense_variant	33/85	1			P78527-2

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000797

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000481

AC:

AN:

249292

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135244

show subpopulations

Gnomad AFR exome

AF:

0.000775

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

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:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000217

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.000797

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000290

Hom.:

Bravo

AF:

0.000287

ESP6500AA

AF:

0.000516

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000745

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 2023

The p.S1409F variant (also known as c.4226C>T), located in coding exon 33 of the PRKDC gene, results from a C to T substitution at nucleotide position 4226. The serine at codon 1409 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is conserved. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Severe combined immunodeficiency due to DNA-PKcs deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2022

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1409 of the PRKDC protein (p.Ser1409Phe). This variant is present in population databases (rs376814572, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with PRKDC-related conditions. ClinVar contains an entry for this variant (Variation ID: 565334). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.33

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

2.9

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.38

REVEL

Benign

0.18

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.85

P;.

Vest4

0.57

MVP

0.62

MPC

0.64

ClinPred

0.67

GERP RS

4.7

Varity_R

0.13

gMVP

0.59

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over