rs8178070

Variant names:

• chr8-47902626-T-C
• rs8178070
• NM_006904.7:c.3212A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006904.7(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. 15/19 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. N1071I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (46 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0360
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• severe combined immunodeficiency due to DNA-PKcs deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006904.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	NM_006904.7	MANE Select	c.3212A>G	p.Asn1071Ser	missense	Exon 27 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.3212A>G	p.Asn1071Ser	missense	Exon 27 of 85	NP_001075109.1	P78527-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	ENST00000314191.7	TSL:1 MANE Select	c.3212A>G	p.Asn1071Ser	missense	Exon 27 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.3212A>G	p.Asn1071Ser	missense	Exon 27 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.3212A>G	p.Asn1071Ser	missense	Exon 27 of 86	ENSP00000581783.1

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

GnomAD2 exomes AF: 0.00368 AC: 911 AN: 247566 AF XY: 0.00283

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 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

African (AFR) AF: 0.0535 AC: 1786 AN: 33402

American (AMR) AF: 0.00176 AC: 78 AN: 44426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39678

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5758

European-Non Finnish (NFE) AF: 0.0000774 AC: 86 AN: 1111014

Other (OTH) AF: 0.00270 AC: 163 AN: 60292

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

African (AFR) AF: 0.0493 AC: 2048 AN: 41552

American (AMR) AF: 0.00392 AC: 60 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68024

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00478 Hom.: 52

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Severe combined immunodeficiency due to DNA-PKcs deficiency (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.036
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.11
Sift	Benign	0.61	T
Sift4G	Benign	0.35	T
Polyphen		0.034	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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs8178070; hg19: chr8-48815186;