8-47799296-C-T

Variant names:

Variant summary

Our verdict is The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BS1BS2BP4_ModerateBP6_Strong

The NM_006904.7(PRKDC):c.10211G>A (p.Gly3404Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0146 (AC=23,615) in the gnomAD database across 1,613,624 control chromosomes, including 230 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0189. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.012 ( 20 hom., cov: 32)

Exomes 𝑓: 0.015 ( 210 hom. )

Consequence

PRKDC
NM_006904.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.02

Publications

11 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: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

PRKDC links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_006904.7, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -14 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BS1

GnomAD effective popmax AF above BS1 threshold — greater than expected for disorder; GnomAD effective popmax AF = 0.0189 vs gene BS1 threshold 0.015.

BS2

≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 230.; Very high cumulative gnomAD AC = 23615 (any gene).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	NM_006904.7	MANE Select	c.10211G>A	p.Gly3404Glu	missense	Exon 72 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.10211G>A	p.Gly3404Glu	missense	Exon 72 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.10211G>A	p.Gly3404Glu	missense	Exon 72 of 86	ENSP00000313420.3	P78527-1
PRKDC	ENST00000338368.7	TSL:1	c.10211G>A	p.Gly3404Glu	missense	Exon 72 of 85	ENSP00000345182.4	P78527-2
PRKDC	ENST00000911724.1		c.10220G>A	p.Gly3407Glu	missense	Exon 72 of 86	ENSP00000581783.1	A0ACI8SJX4

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1822

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00589

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.0233

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0198

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.0115

AC:

2866

AN:

248590

AF XY:

0.0111

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00527

Gnomad ASJ exome

AF:

0.00249

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0238

Gnomad NFE exome

AF:

0.0180

Gnomad OTH exome

AF:

0.00927

GnomAD4 exome

AF:

0.0149

AC:

21794

AN:

1461340

Hom.:

210

Cov.:

AF XY:

0.0144

AC XY:

10492

AN XY:

726952

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

33480

American (AMR)

AF:

0.00572

AC:

256

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00110

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0257

AC:

1363

AN:

53052

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0172

AC:

19102

AN:

1111856

Other (OTH)

AF:

0.0137

AC:

826

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

1210

2421

3631

4842

6052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

660

1320

1980

2640

3300

<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:

0.0120

AC:

1821

AN:

152284

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

916

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00262

AC:

109

AN:

41554

American (AMR)

AF:

0.00589

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000621

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0233

AC:

247

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0198

AC:

1348

AN:

68026

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

188

283

377

471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0153

Hom.:

Bravo

AF:

0.00980

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0150

EpiControl

AF:

0.0161

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.00

AC:

AN:

122790

Turkish Variome

AF:

0.00463

AC:

AN:

6702

Hom.:

ABraOM SABE-WGS-1171

AF:

0.0137

AC:

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Severe combined immunodeficiency due to DNA-PKcs deficiency (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Benign

1.0

(source)

DANN

Benign

0.26

DEOGEN2

Benign

0.043

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0057

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

1.0

PrimateAI

Benign

0.20

REVEL

Benign

0.18

Sift4G

Benign

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.059

gMVP

0.28

Mutation Taster

=94/6

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over