rs8178070

Positions:

• chr8-47902626-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000314191.7(PRKDC):​c.3212A>G​(p.Asn1071Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,612,030 control chromosomes in the GnomAD database, including 93 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1071K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (46 hom.)
• Consequence: PRKDC ENST00000314191.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0360

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=0.0030245185).
• BP6: Variant 8-47902626-T-C is Benign according to our data. Variant chr8-47902626-T-C is described in ClinVar as [Benign]. Clinvar id is 385818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.3212A>G	p.Asn1071Ser	missense_variant	27/86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.3212A>G	p.Asn1071Ser	missense_variant	27/85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.3212A>G	p.Asn1071Ser	missense_variant	27/86	1	NM_006904.7	ENSP00000313420	P1
PRKDC	ENST00000338368.7	c.3212A>G	p.Asn1071Ser	missense_variant	27/85	1		ENSP00000345182

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2137 AN: 152166 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.0493

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00368 AC: 911 AN: 247566 Hom.: 14 AF XY: 0.00283 AC XY: 380 AN XY: 134338

Gnomad AFR exome AF: 0.0531

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000336

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.00146 AC: 2137 AN: 1459746 Hom.: 46 Cov.: 30 AF XY: 0.00128 AC XY: 928 AN XY: 726088

Gnomad4 AFR exome AF: 0.0535

Gnomad4 AMR exome AF: 0.00176

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000774

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.0141 AC: 2140 AN: 152284 Hom.: 47 Cov.: 32 AF XY: 0.0143 AC XY: 1066 AN XY: 74474

Gnomad4 AFR AF: 0.0493

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00261 Hom.: 13

Bravo AF: 0.0159

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0438 AC: 165

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00424 AC: 512

Asia WGS AF: 0.00202 AC: 8 AN: 3478

ClinVar

Significance: 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

May 16, 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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.24
DANN	Benign	0.50
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.11
Sift	Benign	0.61	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.034	B;B
Vest4		0.11
MVP		0.47
MPC		0.13
ClinPred		0.0011	T
GERP RS		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.053
gMVP		0.098

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: rs8178070; hg19: chr8-48815186;