NM_006904.7:c.11222G>A

Variant names:

• chr8-47782552-C-T
• rs759518580
• NM_006904.7:c.11222G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006904.7(PRKDC):​c.11222G>A​(p.Arg3741His) variant causes a missense change. The variant allele was found at a frequency of 0.0000102 in 1,572,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R3741C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.88
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34163827).

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.11222G>A	p.Arg3741His	missense	Exon 79 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.11222G>A	p.Arg3741His	missense	Exon 79 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.11222G>A	p.Arg3741His	missense	Exon 79 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.11222G>A	p.Arg3741His	missense	Exon 79 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.11231G>A	p.Arg3744His	missense	Exon 79 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000213 AC: 4 AN: 187810 AF XY: 0.0000199

Gnomad AFR exome AF: 0.0000931

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000250

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000985 AC: 14 AN: 1420740 Hom.: 0 Cov.: 31 AF XY: 0.0000142 AC XY: 10 AN XY: 702728

African (AFR) AF: 0.0000307 AC: 1 AN: 32576

American (AMR) AF: 0.00 AC: 0 AN: 38458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25432

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37490

South Asian (SAS) AF: 0.0000372 AC: 3 AN: 80710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000825 AC: 9 AN: 1091314

Other (OTH) AF: 0.00 AC: 0 AN: 59014

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

African (AFR) AF: 0.0000483 AC: 2 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000330 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Severe combined immunodeficiency due to DNA-PKcs deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	21
DANN	Benign	0.82
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.095
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.9
PrimateAI	Benign	0.45	T
REVEL	Uncertain	0.44
Sift4G	Benign	0.086	T
Polyphen		0.050	B
Vest4		0.48
MVP		0.87
MPC		0.30
ClinPred		0.59	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.48
gMVP		0.63
Mutation Taster		=61/39	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: rs759518580; hg19: chr8-48695113;