chr8-47939665-C-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.999G>A(p.Met333Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,604,258 control chromosomes in the GnomAD database, including 1,589 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M333T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.031 ( 109 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1480 hom. )

Consequence

PRKDC
NM_006904.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0510

Publications

21 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

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=0.0019012988).

BP6

Variant 8-47939665-C-T is Benign according to our data. Variant chr8-47939665-C-T is described in ClinVar as Benign. ClinVar VariationId is 379752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0307 (4671/152250) while in subpopulation NFE AF = 0.044 (2989/68004). AF 95% confidence interval is 0.0426. There are 109 homozygotes in GnomAd4. There are 2162 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 109 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	NM_006904.7	MANE Select	c.999G>A	p.Met333Ile	missense	Exon 11 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.999G>A	p.Met333Ile	missense	Exon 11 of 85	NP_001075109.1	P78527-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRKDC	ENST00000314191.7	TSL:1 MANE Select	c.999G>A	p.Met333Ile	missense	Exon 11 of 86	ENSP00000313420.3	P78527-1
PRKDC	ENST00000338368.7	TSL:1	c.999G>A	p.Met333Ile	missense	Exon 11 of 85	ENSP00000345182.4	P78527-2
PRKDC	ENST00000911724.1		c.999G>A	p.Met333Ile	missense	Exon 11 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes

AF:

0.0307

AC:

4676

AN:

152132

Hom.:

109

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00758

Gnomad AMI

AF:

0.0187

Gnomad AMR

AF:

0.0325

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00934

Gnomad FIN

AF:

0.0266

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0439

Gnomad OTH

AF:

0.0459

GnomAD2 exomes

AF:

0.0335

AC:

8026

AN:

239834

AF XY:

0.0341

show subpopulations

Gnomad AFR exome

AF:

0.00642

Gnomad AMR exome

AF:

0.0270

Gnomad ASJ exome

AF:

0.113

Gnomad EAS exome

AF:

0.000170

Gnomad FIN exome

AF:

0.0268

Gnomad NFE exome

AF:

0.0441

Gnomad OTH exome

AF:

0.0467

GnomAD4 exome

AF:

0.0399

AC:

57965

AN:

1452008

Hom.:

1480

Cov.:

AF XY:

0.0391

AC XY:

28217

AN XY:

721648

show subpopulations

African (AFR)

AF:

0.00664

AC:

220

AN:

33108

American (AMR)

AF:

0.0271

AC:

1157

AN:

42762

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

2957

AN:

25832

East Asian (EAS)

AF:

0.000101

AC:

AN:

39608

South Asian (SAS)

AF:

0.0101

AC:

846

AN:

83524

European-Finnish (FIN)

AF:

0.0285

AC:

1519

AN:

53294

Middle Eastern (MID)

AF:

0.0539

AC:

309

AN:

5732

European-Non Finnish (NFE)

AF:

0.0436

AC:

48294

AN:

1108048

Other (OTH)

AF:

0.0442

AC:

2659

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

2560

5120

7681

10241

12801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1762

3524

5286

7048

8810

<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:

0.0307

AC:

4671

AN:

152250

Hom.:

109

Cov.:

AF XY:

0.0290

AC XY:

2162

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00753

AC:

313

AN:

41554

American (AMR)

AF:

0.0323

AC:

494

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

412

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.00934

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0266

AC:

282

AN:

10608

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0440

AC:

2989

AN:

68004

Other (OTH)

AF:

0.0455

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

240

481

721

962

1202

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0427

Hom.:

504

Bravo

AF:

0.0306

TwinsUK

AF:

0.0375

AC:

139

ALSPAC

AF:

0.0444

AC:

171

ESP6500AA

AF:

0.00436

AC:

ESP6500EA

AF:

0.0453

AC:

370

ExAC

AF:

0.0314

AC:

3796

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Severe combined immunodeficiency due to DNA-PKcs deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.068

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.1

PhyloP100

0.051

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.60

REVEL

Benign

0.13

Sift

Benign

0.39

Sift4G

Benign

0.20

Polyphen

0.0010

Vest4

0.074

MutPred

0.15

Loss of ubiquitination at K335 (P = 0.0533)

MPC

0.18

ClinPred

0.0013

GERP RS

1.7

Varity_R

0.15

gMVP

0.086

Mutation Taster

=99/1

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over