rs202110076

Positions:

chr8-47879606-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006904.7(PRKDC):c.5120T>A(p.Leu1707Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,592,820 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 11 hom. )

Consequence

PRKDC
NM_006904.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 8.60

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]

PRKDC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0539065).

BP6

Variant 8-47879606-A-T is Benign according to our data. Variant chr8-47879606-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 429510.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKDC	NM_006904.7 linkuse as main transcript	c.5120T>A	p.Leu1707Gln	missense_variant	39/86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2 linkuse as main transcript	c.5120T>A	p.Leu1707Gln	missense_variant	39/85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7 linkuse as main transcript	c.5120T>A	p.Leu1707Gln	missense_variant	39/86	1	NM_006904.7	ENSP00000313420	P1	P78527-1
PRKDC	ENST00000338368.7 linkuse as main transcript	c.5120T>A	p.Leu1707Gln	missense_variant	39/85	1		ENSP00000345182		P78527-2

Frequencies

GnomAD3 genomes

AF:

0.00225

AC:

342

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00416

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00208

AC:

450

AN:

216556

Hom.:

AF XY:

0.00216

AC XY:

252

AN XY:

116410

show subpopulations

Gnomad AFR exome

AF:

0.000535

Gnomad AMR exome

AF:

0.000837

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000948

Gnomad FIN exome

AF:

0.000448

Gnomad NFE exome

AF:

0.00380

Gnomad OTH exome

AF:

0.00258

GnomAD4 exome

AF:

0.00336

AC:

4837

AN:

1440502

Hom.:

Cov.:

AF XY:

0.00331

AC XY:

2365

AN XY:

714264

show subpopulations

Gnomad4 AFR exome

AF:

0.000364

Gnomad4 AMR exome

AF:

0.00111

Gnomad4 ASJ exome

AF:

0.000273

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000787

Gnomad4 FIN exome

AF:

0.000667

Gnomad4 NFE exome

AF:

0.00411

Gnomad4 OTH exome

AF:

0.00229

GnomAD4 genome

AF:

0.00225

AC:

342

AN:

152318

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

143

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00416

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00402

Hom.:

Bravo

AF:

0.00208

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000252

AC:

ESP6500EA

AF:

0.00348

AC:

ExAC

AF:

0.00199

AC:

241

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Severe combined immunodeficiency due to DNA-PKcs deficiency

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 24, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2020	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PRKDC: BP4 -

PRKDC-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.060

MetaRNN

Benign

0.054

T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Pathogenic

2.9

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.45

REVEL

Uncertain

0.40

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.91

MVP

0.90

MPC

0.69

ClinPred

0.047

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.64

gMVP

0.39

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