8-47774280-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006904.7(PRKDC):c.12280C>T(p.Pro4094Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PRKDC
NM_006904.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.78

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

severe combined immunodeficiency due to DNA-PKcs deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

PRKDC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10326436).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7 link	c.12280C>T	p.Pro4094Ser	missense_variant	Exon 86 of 86	ENST00000314191.7	NP_008835.5	P78527-1
PRKDC	NM_001081640.2 link	c.12187C>T	p.Pro4063Ser	missense_variant	Exon 85 of 85		NP_001075109.1	P78527-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7 link	c.12280C>T	p.Pro4094Ser	missense_variant	Exon 86 of 86	1	NM_006904.7	ENSP00000313420.3		P78527-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000408

AC:

AN:

244914

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000899

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459302

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725542

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26010

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

85408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111016

Other (OTH)

AF:

0.00

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Severe combined immunodeficiency due to DNA-PKcs deficiency

Uncertain:1

Feb 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is present in population databases (rs748067036, gnomAD 0.0009%). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with PRKDC-related conditions. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 4094 of the PRKDC protein (p.Pro4094Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.0079

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

M;.

PhyloP100

3.8

PrimateAI

Benign

0.34

REVEL

Benign

0.11

Sift4G

Uncertain

0.026

D;D

Polyphen

0.019

B;.

Vest4

0.12

MutPred

0.15

Gain of phosphorylation at P4094 (P = 0.0452);.;

MVP

0.58

MPC

0.47

ClinPred

0.90

GERP RS

4.7

Varity_R

0.25

gMVP

0.59

Mutation Taster

=88/12

polymorphism

(source)

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

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8-47774280-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over