chr8-47939665-C-T

Position:

chr8-47939665-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

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:

PRKDC (HGNC:):

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=0.0019012988).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 109 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKDC	NM_006904.7 linkuse as main transcript	c.999G>A	p.Met333Ile	missense_variant	11/86	ENST00000314191.7	NP_008835.5	P78527-1
PRKDC	NM_001081640.2 linkuse as main transcript	c.999G>A	p.Met333Ile	missense_variant	11/85		NP_001075109.1	P78527-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PRKDC	ENST00000314191.7 linkuse as main transcript	c.999G>A	p.Met333Ile	missense_variant	11/86	1	NM_006904.7	ENSP00000313420.3	P78527-1
PRKDC	ENST00000338368.7 linkuse as main transcript	c.999G>A	p.Met333Ile	missense_variant	11/85	1		ENSP00000345182.4	P78527-2
PRKDC	ENST00000535375.1 linkuse as main transcript	n.286G>A		non_coding_transcript_exon_variant	1/2	3
PRKDC	ENST00000697591.1 linkuse as main transcript	n.1040G>A		non_coding_transcript_exon_variant	11/15

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

GnomAD3 exomes

AF:

0.0335

AC:

8026

AN:

239834

Hom.:

226

AF XY:

0.0341

AC XY:

4434

AN XY:

129934

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 SAS exome

AF:

0.00966

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

Gnomad4 AFR exome

AF:

0.00664

Gnomad4 AMR exome

AF:

0.0271

Gnomad4 ASJ exome

AF:

0.114

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0101

Gnomad4 FIN exome

AF:

0.0285

Gnomad4 NFE exome

AF:

0.0436

Gnomad4 OTH exome

AF:

0.0442

GnomAD4 genome

AF:

0.0307

AC:

4671

AN:

152250

Hom.:

109

Cov.:

AF XY:

0.0290

AC XY:

2162

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00753

Gnomad4 AMR

AF:

0.0323

Gnomad4 ASJ

AF:

0.119

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00934

Gnomad4 FIN

AF:

0.0266

Gnomad4 NFE

AF:

0.0440

Gnomad4 OTH

AF:

0.0455

Alfa

AF:

0.0443

Hom.:

420

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Severe combined immunodeficiency due to DNA-PKcs deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.068

T;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.60

N;N

REVEL

Benign

0.13

Sift

Benign

0.39

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.0010

B;B

Vest4

0.074

MutPred

0.15

Loss of ubiquitination at K335 (P = 0.0533);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

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