rs202110076

chr8-47879606-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006904.7(PRKDC):c.5120T>A(p.Leu1707Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,592,820 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (11 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 8.60

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0539065).
• BP6: Variant 8-47879606-A-T is Benign according to our data. Variant chr8-47879606-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 429510.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.5120T>A	p.Leu1707Gln	missense_variant	39/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.5120T>A	p.Leu1707Gln	missense_variant	39/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.5120T>A	p.Leu1707Gln	missense_variant	39/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.5120T>A	p.Leu1707Gln	missense_variant	39/85	1

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 342 AN: 152200 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00416

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00208 AC: 450 AN: 216556 Hom.: 0 AF XY: 0.00216 AC XY: 252 AN XY: 116410

Gnomad AFR exome AF: 0.000535

Gnomad AMR exome AF: 0.000837

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000948

Gnomad FIN exome AF: 0.000448

Gnomad NFE exome AF: 0.00380

Gnomad OTH exome AF: 0.00258

GnomAD4 exome AF: 0.00336 AC: 4837 AN: 1440502 Hom.: 11 Cov.: 31 AF XY: 0.00331 AC XY: 2365 AN XY: 714264

Gnomad4 AFR exome AF: 0.000364

Gnomad4 AMR exome AF: 0.00111

Gnomad4 ASJ exome AF: 0.000273

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000787

Gnomad4 FIN exome AF: 0.000667

Gnomad4 NFE exome AF: 0.00411

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00225 AC: 342 AN: 152318 Hom.: 2 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74470

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00416

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00402 Hom.: 2

Bravo AF: 0.00208

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000252 AC: 1

ESP6500EA AF: 0.00348 AC: 29

ExAC AF: 0.00199 AC: 241

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe combined immunodeficiency due to DNA-PKcs deficiency Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 24, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2020	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PRKDC: BP4 -

PRKDC-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.054	T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	2.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
REVEL	Uncertain	0.40
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.91
MVP		0.90
MPC		0.69
ClinPred		0.047	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.64
gMVP		0.39

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: rs202110076; hg19: chr8-48792167; COSMIC: COSV100040054;