rs8178228

chr8-47798319-T-C

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.10376A>G(p.Asn3459Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,613,610 control chromosomes in the GnomAD database, including 56 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (28 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0500

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=0.0017743111).
• BP6: Variant 8-47798319-T-C is Benign according to our data. Variant chr8-47798319-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 376992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00998 (1521/152348) while in subpopulation AFR AF= 0.0338 (1404/41592). AF 95% confidence interval is 0.0323. There are 28 homozygotes in gnomad4. There are 709 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.10376A>G	p.Asn3459Ser	missense_variant	73/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.10376A>G	p.Asn3459Ser	missense_variant	73/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.10376A>G	p.Asn3459Ser	missense_variant	73/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.10376A>G	p.Asn3459Ser	missense_variant	73/85	1
PRKDC	ENST00000697603.1	c.3053A>G	p.Asn1018Ser	missense_variant	20/33
PRKDC	ENST00000697602.1	n.949A>G		non_coding_transcript_exon_variant	5/18

Frequencies

GnomAD3 genomes AF: 0.00999 AC: 1521 AN: 152230 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00250 AC: 620 AN: 248052 Hom.: 11 AF XY: 0.00195 AC XY: 263 AN XY: 134650

Gnomad AFR exome AF: 0.0335

Gnomad AMR exome AF: 0.00233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.000996

GnomAD4 exome AF: 0.00105 AC: 1532 AN: 1461262 Hom.: 28 Cov.: 30 AF XY: 0.000893 AC XY: 649 AN XY: 726878

Gnomad4 AFR exome AF: 0.0350

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00998 AC: 1521 AN: 152348 Hom.: 28 Cov.: 32 AF XY: 0.00952 AC XY: 709 AN XY: 74504

Gnomad4 AFR AF: 0.0338

Gnomad4 AMR AF: 0.00614

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00211 Hom.: 6

Bravo AF: 0.0115

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0370 AC: 135

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00287 AC: 347

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2017

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, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jan 10, 2017

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.81
Dann	Benign	0.19
DEOGEN2	Benign	0.041	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.75	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.90	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
REVEL	Benign	0.062
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.064
MVP		0.37
MPC		0.13
ClinPred		0.00043	T
GERP RS		-7.8
Varity_R		0.035
gMVP		0.028

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: rs8178228; hg19: chr8-48710880;