rs1000728174

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006904.7(PRKDC):c.2112T>A(p.Phe704Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,574,826 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 (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

PRKDC
NM_006904.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.15

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24194616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7 linkuse as main transcript	c.2112T>A	p.Phe704Leu	missense_variant	19/86	ENST00000314191.7
PRKDC	NM_001081640.2 linkuse as main transcript	c.2112T>A	p.Phe704Leu	missense_variant	19/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7 linkuse as main transcript	c.2112T>A	p.Phe704Leu	missense_variant	19/86	1	NM_006904.7	P1	P78527-1
PRKDC	ENST00000338368.7 linkuse as main transcript	c.2112T>A	p.Phe704Leu	missense_variant	19/85	1			P78527-2
PRKDC	ENST00000541488.1 linkuse as main transcript	n.51T>A		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000103

AC:

AN:

193946

Hom.:

AF XY:

0.00

AC XY:

AN XY:

103196

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000344

AC:

AN:

1422558

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

703710

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000431

Gnomad4 OTH exome

AF:

0.0000339

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000189

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

Sep 22, 2023

The c.2112T>A (p.F704L) alteration is located in exon 19 (coding exon 19) of the PRKDC gene. This alteration results from a T to A substitution at nucleotide position 2112, causing the phenylalanine (F) at amino acid position 704 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, 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

Invitae

Jun 20, 2023

This variant has not been reported in the literature in individuals affected with PRKDC-related conditions. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRKDC protein function. ClinVar contains an entry for this variant (Variation ID: 541990). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 704 of the PRKDC protein (p.Phe704Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.27

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-0.81

MutationTaster

Benign

0.97

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.9

D;D

REVEL

Benign

0.11

Sift

Uncertain

0.0060

D;D

Sift4G

Benign

0.17

T;T

Polyphen

0.10

B;B

Vest4

0.47

MutPred

0.36

Gain of catalytic residue at F704 (P = 0.0461);Gain of catalytic residue at F704 (P = 0.0461);

MVP

0.71

MPC

0.48

ClinPred

0.83

GERP RS

2.9

Varity_R

0.18

gMVP

0.62

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