rs147314874

Variant names:

• chr8-47934063-G-A
• rs147314874
• NM_006904.7:c.1525C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-47934063-G-A
• chr8-47934063-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006904.7(PRKDC):​c.1525C>T​(p.Arg509Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,613,582 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R509H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.644
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02349329).

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.1525C>T	p.Arg509Cys	missense	Exon 15 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.1525C>T	p.Arg509Cys	missense	Exon 15 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.1525C>T	p.Arg509Cys	missense	Exon 15 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.1525C>T	p.Arg509Cys	missense	Exon 15 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.1525C>T	p.Arg509Cys	missense	Exon 15 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000285 AC: 71 AN: 249038 AF XY: 0.000363

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000283 AC: 414 AN: 1461336 Hom.: 1 Cov.: 33 AF XY: 0.000319 AC XY: 232 AN XY: 726946

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.000112 AC: 5 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00107 AC: 92 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5752

European-Non Finnish (NFE) AF: 0.000246 AC: 274 AN: 1111634

Other (OTH) AF: 0.000364 AC: 22 AN: 60358

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74454

African (AFR) AF: 0.0000241 AC: 1 AN: 41554

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68004

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000156 Hom.: 0

Bravo AF: 0.000132

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000281 AC: 34

EpiCase AF: 0.000437

EpiControl AF: 0.000534

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	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	0.088
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.94	T
PhyloP100		0.64
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.019
Sift	Benign	0.18	T
Sift4G	Benign	0.19	T
Polyphen		0.0020	B
Vest4		0.32
MVP		0.24
MPC		0.64
ClinPred		0.037	T
GERP RS		2.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.15
gMVP		0.17
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs147314874; hg19: chr8-48846623;