NM_006904.7:c.1814C>G

Variant names:

• chr8-47930750-G-C
• rs8178033
• NM_006904.7:c.1814C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006904.7(PRKDC):​c.1814C>G​(p.Thr605Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,590,022 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T605A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (144 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (126 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.32
• Publications: 12 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019198656).
• BP6: Variant 8-47930750-G-C is Benign according to our data. Variant chr8-47930750-G-C is described in ClinVar as Benign. ClinVar VariationId is 475221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0777 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	NM_006904.7	MANE Select	c.1814C>G	p.Thr605Ser	missense	Exon 17 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.1814C>G	p.Thr605Ser	missense	Exon 17 of 85	NP_001075109.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	ENST00000314191.7	TSL:1 MANE Select	c.1814C>G	p.Thr605Ser	missense	Exon 17 of 86	ENSP00000313420.3
	PRKDC	ENST00000338368.7	TSL:1	c.1814C>G	p.Thr605Ser	missense	Exon 17 of 85	ENSP00000345182.4

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3547 AN: 152146 Hom.: 145 Cov.: 32

Gnomad AFR AF: 0.0803

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.00623 AC: 1319 AN: 211630 AF XY: 0.00466

Gnomad AFR exome AF: 0.0850

Gnomad AMR exome AF: 0.00617

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000152

Gnomad NFE exome AF: 0.000483

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00251 AC: 3611 AN: 1437758 Hom.: 126 Cov.: 30 AF XY: 0.00213 AC XY: 1520 AN XY: 712640

African (AFR) AF: 0.0816 AC: 2679 AN: 32848

American (AMR) AF: 0.00661 AC: 273 AN: 41332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25630

East Asian (EAS) AF: 0.00 AC: 0 AN: 38892

South Asian (SAS) AF: 0.000159 AC: 13 AN: 81806

European-Finnish (FIN) AF: 0.0000576 AC: 3 AN: 52060

Middle Eastern (MID) AF: 0.00522 AC: 30 AN: 5748

European-Non Finnish (NFE) AF: 0.000255 AC: 281 AN: 1099842

Other (OTH) AF: 0.00557 AC: 332 AN: 59600

GnomAD4 genome AF: 0.0233 AC: 3543 AN: 152264 Hom.: 144 Cov.: 32 AF XY: 0.0221 AC XY: 1649 AN XY: 74462

African (AFR) AF: 0.0800 AC: 3321 AN: 41526

American (AMR) AF: 0.0103 AC: 157 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68014

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.00411 Hom.: 13

Bravo AF: 0.0262

ESP6500AA AF: 0.0815 AC: 303

ESP6500EA AF: 0.000610 AC: 5

ExAC AF: 0.00663 AC: 799

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jan 16, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Severe combined immunodeficiency due to DNA-PKcs deficiency Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.62	T
PhyloP100		9.3
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.18
Sift	Benign	0.36	T
Sift4G	Benign	0.60	T
Polyphen		0.29	B
Vest4		0.17
MutPred		0.22		Loss of glycosylation at T605 (P = 0.0401)
MVP		0.36
MPC		0.21
ClinPred		0.055	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.19
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs8178033; hg19: chr8-48843310; COSMIC: COSV104628435;