rs8178017

chr8-47939665-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/17 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0510

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 109 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.999G>A	p.Met333Ile	missense_variant	11/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.999G>A	p.Met333Ile	missense_variant	11/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.999G>A	p.Met333Ile	missense_variant	11/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.999G>A	p.Met333Ile	missense_variant	11/85	1
PRKDC	ENST00000535375.1	n.286G>A		non_coding_transcript_exon_variant	1/2	3
PRKDC	ENST00000697591.1	n.1040G>A		non_coding_transcript_exon_variant	11/15

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 4676 AN: 152132 Hom.: 109 Cov.: 32

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

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.: 30 AF XY: 0.0391 AC XY: 28217 AN XY: 721648

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.: 32 AF XY: 0.0290 AC XY: 2162 AN XY: 74434

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: 16

ESP6500EA AF: 0.0453 AC: 370

ExAC AF: 0.0314 AC: 3796

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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. -

not provided Benign:1

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	14
Dann	Benign	0.94
DEOGEN2	Benign	0.068	T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
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	T
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

Other links and lift over

dbSNP: rs8178017; hg19: chr8-48852225; COSMIC: COSV104628405;