chr8-47799296-C-T

Variant names:

• chr8-47799296-C-T
• rs8178225
• NM_006904.7:c.10211G>A
• PRKDC p.Gly3404Glu

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BS1BS2BP4_ModerateBP6_Strong

The NM_006904.7(PRKDC):c.10211G>A (p.Gly3404Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0146 (AC=23,615) in the gnomAD database across 1,613,624 control chromosomes, including 230 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0189. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.012 (20 hom., cov: 32)
  • Exomes 𝑓: 0.015 (210 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.02
• Publications: 11 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BS1Allele frequency higher than expected		GnomAD effective popmax AF above BS1 threshold — greater than expected for disorder; GnomAD effective popmax AF = 0.0189 vs gene BS1 threshold 0.015.
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 230.; Very high cumulative gnomAD AC = 23615 (any gene).

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>A p.Gly3404Glu	missense	Exon 72 of 86	Prot: NP_008835.5
	PRKDC NM_001081640.2		c.10211G>A p.Gly3404Glu	missense	Exon 72 of 85	Prot: NP_001075109.1 UniProt:

PRKDC NM_006904.7

MANE Select

HGVSc / HGVSpc.10211G>Ap.Gly3404Glu

Exon rankExon 72 of 86

missense

Prot: NP_008835.5

PRKDC NM_001081640.2

HGVSc / HGVSpc.10211G>Ap.Gly3404Glu

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>A p.Gly3404Glu	missense	Exon 72 of 86	Prot: ENSP00000313420.3 UniProt:
	PRKDC ENST00000338368.7	TSL:1	c.10211G>A p.Gly3404Glu	missense	Exon 72 of 85	Prot: ENSP00000345182.4 UniProt:
	PRKDC ENST00000911724.1		c.10220G>A p.Gly3407Glu	missense	Exon 72 of 86	Prot: ENSP00000581783.1 UniProt:

PRKDC ENST00000314191.7

TSL:1MANE Select

HGVSc / HGVSpc.10211G>Ap.Gly3404Glu

Exon rankExon 72 of 86

missense

Prot: ENSP00000313420.3UniProt: P78527-1

PRKDC ENST00000338368.7

TSL:1

HGVSc / HGVSpc.10211G>Ap.Gly3404Glu

Exon rankExon 72 of 85

missense

Prot: ENSP00000345182.4UniProt: P78527-2

PRKDC ENST00000911724.1

HGVSc / HGVSpc.10220G>Ap.Gly3407Glu

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0120	AC:1822	Hom:20	AN:152166	Cov:32
GnomAD2 exomes	AF: 0.0115	AC:2866	Hom:	AN:248590	Cov:
GnomAD4 exome	AF: 0.0149	AC:21794	Hom:210	AN:1461340	Cov:30
GnomAD4 genome	AF: 0.0120	AC:1821	Hom:20	AN:152284	Cov:32
TOPMed (Bravo)	AF: 0.00980	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0151	AC:4949	Hom:56	AN:327150	Cov:
Local & regional cohorts 7 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0137	AC:32	Hom:1	AN:2342	Cov:
Denmark Genome	AF: 0.0367	AC:11	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0141	AC:174	Hom:	AN:12374	Cov:
GenomeAsia100K	AF: 0.00115	AC:4	Hom:	AN:3478	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00	AC:0	Hom:0	AN:122790	Cov:
Turkish Variome	AF: 0.00463	AC:31	Hom:0	AN:6702	Cov:
UK10K	AF: 0.0172	AC:130	Hom:	AN:7562	Cov:

Showing 13 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0190 *	207	10906	0.0167 *	290	17390
BipEx(Bipolar disorder (including schizoaffective))	0.0182	517	28418	0.0187	540	28844
Epi25(Epilepsy)	0.0145	610	41958	0.0148	988	66888
SCHEMA(Schizophrenia)	0.0114	1386	122036	0.0140	2696	192394

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Severe combined immunodeficiency due to DNA-PKcs deficiency (2)
-	-	1	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	7.7
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.0
DANN	Benign	0.26
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
FuncVEP CTI	Benign	0.00061
GPN-Star LLR	N/A	-0.69
GPN-Star score	N/A	0.69
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	94/6	polymorphism
MutationAssessor	Benign	1.1	L
PhyloP100	Benign	1.0
PrimateAI	Benign	0.20	T
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.8
REVEL	Benign	0.18
Sift4G	Benign	1.0	T
Varity_R	N/A	0.059
VESM-3B	Benign	-5.5

Showing 26 of 26 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