Genetic Variant PRKDC:p.Pro4114Ser (chr8-47774220-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006904.7(PRKDC):c.12340C>T(p.Pro4114Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,344 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PRKDC
NM_006904.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.63

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7 link	c.12340C>T	p.Pro4114Ser	missense_variant	Exon 86 of 86	ENST00000314191.7	NP_008835.5	P78527-1
PRKDC	NM_001081640.2 link	c.12247C>T	p.Pro4083Ser	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.12340C>T	p.Pro4114Ser	missense_variant	Exon 86 of 86	1	NM_006904.7	ENSP00000313420.3		P78527-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1445344

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33258

American (AMR)

AF:

0.00

AC:

AN:

41724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25654

East Asian (EAS)

AF:

0.00

AC:

AN:

39354

South Asian (SAS)

AF:

0.00

AC:

AN:

83298

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1103886

Other (OTH)

AF:

0.00

AC:

AN:

59856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 02, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P4114S variant (also known as c.12340C>T), located in coding exon 86 of the PRKDC gene, results from a C to T substitution at nucleotide position 12340. The proline at codon 4114 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

7.6

PrimateAI

Uncertain

0.58

REVEL

Pathogenic

0.80

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.98

D;.

Vest4

0.53

MutPred

0.56

Gain of MoRF binding (P = 0.1449);.;

MVP

0.77

MPC

0.67

ClinPred

0.96

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.24

gMVP

0.88

Mutation Taster

=55/45

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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8-47774220-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