8-47799296-C-G

Variant names:

• chr8-47799296-C-G
• rs8178225
• NM_006904.7:c.10211G>C
• PRKDC p.Gly3404Ala

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateB3_Supporting

The NM_006904.7(PRKDC):c.10211G>C (p.Gly3404Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene PRKDC is a tumor suppressor gene (CancerMine: 3 TSG, 11 oncogene, 7 driver citations). The gene PRKDC is a known oncogene (CancerMine: 3 TSG, 11 oncogene, 7 driver citations). The gene PRKDC is a cancer driver gene (CancerMine: 3 TSG, 11 oncogene, 7 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G3404E: Benign/Likely_benign (ClinVar VariationId 379650, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• 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: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PRKDC NM_006904.7	MANE Select	c.10211G>C p.Gly3404Ala	missense	Exon 72 of 86	Prot: NP_008835.5
	PRKDC NM_001081640.2		c.10211G>C p.Gly3404Ala	missense	Exon 72 of 85	Prot: NP_001075109.1 UniProt:

PRKDC NM_006904.7

MANE Select

HGVSc / HGVSpc.10211G>Cp.Gly3404Ala

Exon rankExon 72 of 86

missense

Prot: NP_008835.5

PRKDC NM_001081640.2

HGVSc / HGVSpc.10211G>Cp.Gly3404Ala

Exon rankExon 72 of 85

missense

Prot: NP_001075109.1UniProt: P78527-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PRKDC ENST00000314191.7	TSL:1MANE Select	c.10211G>C p.Gly3404Ala	missense	Exon 72 of 86	Prot: ENSP00000313420.3 UniProt:
	PRKDC ENST00000338368.7	TSL:1	c.10211G>C p.Gly3404Ala	missense	Exon 72 of 85	Prot: ENSP00000345182.4 UniProt:
	PRKDC ENST00000911724.1		c.10220G>C p.Gly3407Ala	missense	Exon 72 of 86	Prot: ENSP00000581783.1 UniProt:

PRKDC ENST00000314191.7

TSL:1MANE Select

HGVSc / HGVSpc.10211G>Cp.Gly3404Ala

Exon rankExon 72 of 86

missense

Prot: ENSP00000313420.3UniProt: P78527-1

PRKDC ENST00000338368.7

TSL:1

HGVSc / HGVSpc.10211G>Cp.Gly3404Ala

Exon rankExon 72 of 85

missense

Prot: ENSP00000345182.4UniProt: P78527-2

PRKDC ENST00000911724.1

HGVSc / HGVSpc.10220G>Cp.Gly3407Ala

Exon rankExon 72 of 86

missense

Prot: ENSP00000581783.1UniProt: A0ACI8SJX4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	8.2
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.54
DANN	Benign	0.28
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
FuncVEP CTI	Benign	0.0026
GPN-Star LLR	N/A	-0.66
GPN-Star score	N/A	0.66
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.97	T
Mutation Taster	N/A	94/6	polymorphism
MutationAssessor	Benign	1.8	L
PhyloP100	Benign	1.0
PrimateAI	Benign	0.19	T
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.8
REVEL	Benign	0.19
Sift4G	Benign	0.76	T
Varity_R	N/A	0.055
VESM-3B	Benign	-3.9

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs8178225;

hg19: chr8-48711857;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar