rs199908344

Variant names:

• chr8-47858869-C-T
• rs199908344
• NM_006904.7:c.6325G>A
• PRKDC p.Gly2109Ser

Variant summary

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

The NM_006904.7(PRKDC):​c.6325G>A​(p.Gly2109Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G2109G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.966
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007293254).

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.6325G>A	p.Gly2109Ser	missense	Exon 47 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.6325G>A	p.Gly2109Ser	missense	Exon 47 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.6325G>A	p.Gly2109Ser	missense	Exon 47 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.6325G>A	p.Gly2109Ser	missense	Exon 47 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.6325G>A	p.Gly2109Ser	missense	Exon 47 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152108 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000285 AC: 71 AN: 248844 AF XY: 0.000304

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00145

Gnomad FIN exome AF: 0.00149

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000116 AC: 170 AN: 1461494 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 98 AN XY: 727030

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00141 AC: 56 AN: 39690

South Asian (SAS) AF: 0.000394 AC: 34 AN: 86256

European-Finnish (FIN) AF: 0.000956 AC: 51 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111774

Other (OTH) AF: 0.000149 AC: 9 AN: 60366

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74444

African (AFR) AF: 0.00 AC: 0 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5168

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

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000945

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	5.2
DANN	Benign	0.67
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.97
PrimateAI	Benign	0.26	T
REVEL	Benign	0.018
Sift4G	Benign	0.52	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.034
gMVP		0.47
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs199908344;

hg19: chr8-48771430;