8-47789225-A-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006904.7(PRKDC):c.10684T>A(p.Leu3562Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,585,258 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L3562F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0048 ( 16 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 59 hom. )

Consequence

PRKDC
NM_006904.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.727

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005986452).

BP6

Variant 8-47789225-A-T is Benign according to our data. Variant chr8-47789225-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 440194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00478 (727/151970) while in subpopulation AMR AF= 0.0346 (528/15252). AF 95% confidence interval is 0.0322. There are 16 homozygotes in gnomad4. There are 443 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7 link	c.10684T>A	p.Leu3562Met	missense_variant	Exon 75 of 86	ENST00000314191.7	NP_008835.5	P78527-1
PRKDC	NM_001081640.2 link	c.10684T>A	p.Leu3562Met	missense_variant	Exon 75 of 85		NP_001075109.1	P78527-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRKDC	ENST00000314191.7 link	c.10684T>A	p.Leu3562Met	missense_variant	Exon 75 of 86	1	NM_006904.7	ENSP00000313420.3	P78527-1
PRKDC	ENST00000338368.7 link	c.10684T>A	p.Leu3562Met	missense_variant	Exon 75 of 85	1		ENSP00000345182.4	P78527-2
PRKDC	ENST00000697603.1 link	c.3361T>A	p.Leu1121Met	missense_variant	Exon 22 of 33			ENSP00000513358.1	A0A8V8TMR1
PRKDC	ENST00000697602.1 link	n.1257T>A		non_coding_transcript_exon_variant	Exon 7 of 18

Frequencies

GnomAD3 genomes

AF:

0.00479

AC:

727

AN:

151864

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0347

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0298

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00746

AC:

1697

AN:

227604

Hom.:

AF XY:

0.00594

AC XY:

736

AN XY:

123854

show subpopulations

Gnomad AFR exome

AF:

0.000335

Gnomad AMR exome

AF:

0.0388

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0344

Gnomad SAS exome

AF:

0.000395

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000839

Gnomad OTH exome

AF:

0.00314

GnomAD4 exome

AF:

0.00196

AC:

2813

AN:

1433288

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

1268

AN XY:

712080

show subpopulations

Gnomad4 AFR exome

AF:

0.000308

Gnomad4 AMR exome

AF:

0.0355

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0305

Gnomad4 SAS exome

AF:

0.000687

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000445

Gnomad4 OTH exome

AF:

0.00196

GnomAD4 genome

AF:

0.00478

AC:

727

AN:

151970

Hom.:

Cov.:

AF XY:

0.00596

AC XY:

443

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.000458

Gnomad4 AMR

AF:

0.0346

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0301

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00147

Hom.:

Bravo

AF:

0.00677

ESP6500AA

AF:

0.00112

AC:

ESP6500EA

AF:

0.000246

AC:

ExAC

AF:

0.00592

AC:

715

Asia WGS

AF:

0.0120

AC:

AN:

3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Severe combined immunodeficiency due to DNA-PKcs deficiency

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;.

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0060

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

3.0

M;M

PrimateAI

Uncertain

0.50

REVEL

Benign

0.10

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.41

MVP

0.86

MPC

0.68

ClinPred

0.091

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.53

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