8-47789225-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

12 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006904.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	NM_006904.7	MANE Select	c.10684T>A	p.Leu3562Met	missense	Exon 75 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.10684T>A	p.Leu3562Met	missense	Exon 75 of 85	NP_001075109.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRKDC	ENST00000314191.7	TSL:1 MANE Select	c.10684T>A	p.Leu3562Met	missense	Exon 75 of 86	ENSP00000313420.3
PRKDC	ENST00000338368.7	TSL:1	c.10684T>A	p.Leu3562Met	missense	Exon 75 of 85	ENSP00000345182.4
PRKDC	ENST00000697603.1		c.3361T>A	p.Leu1121Met	missense	Exon 22 of 33	ENSP00000513358.1

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

GnomAD2 exomes

AF:

0.00746

AC:

1697

AN:

227604

AF XY:

0.00594

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 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

African (AFR)

AF:

0.000308

AC:

AN:

32432

American (AMR)

AF:

0.0355

AC:

1382

AN:

38914

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25170

East Asian (EAS)

AF:

0.0305

AC:

1200

AN:

39320

South Asian (SAS)

AF:

0.000687

AC:

AN:

78590

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52578

Middle Eastern (MID)

AF:

0.000360

AC:

AN:

5550

European-Non Finnish (NFE)

AF:

0.0000445

AC:

AN:

1101630

Other (OTH)

AF:

0.00196

AC:

116

AN:

59104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

119

239

358

478

597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00478

AC:

727

AN:

151970

Hom.:

Cov.:

AF XY:

0.00596

AC XY:

443

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

41522

American (AMR)

AF:

0.0346

AC:

528

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0301

AC:

156

AN:

5186

South Asian (SAS)

AF:

0.00104

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67936

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Sep 27, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0060

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

3.0

PhyloP100

0.73

PrimateAI

Uncertain

0.50

REVEL

Benign

0.10

Sift4G

Pathogenic

0.0

Polyphen

1.0

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

Mutation Taster

=98/2

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over