NM_006904.7:c.4809G>T

Variant names:

• chr8-47882065-C-A
• rs8178106
• NM_006904.7:c.4809G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006904.7(PRKDC):​c.4809G>T​(p.Gln1603His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000842 in 1,613,976 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 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. Q1603R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00081 (20 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.678
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008693606).
• BP6: Variant 8-47882065-C-A is Benign according to our data. Variant chr8-47882065-C-A is described in ClinVar as Benign. ClinVar VariationId is 379756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000811 (1186/1461640) while in subpopulation AMR AF = 0.0258 (1155/44708). AF 95% confidence interval is 0.0246. There are 20 homozygotes in GnomAdExome4. There are 498 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.4809G>T	p.Gln1603His	missense	Exon 37 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.4809G>T	p.Gln1603His	missense	Exon 37 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.4809G>T	p.Gln1603His	missense	Exon 37 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.4809G>T	p.Gln1603His	missense	Exon 37 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.4809G>T	p.Gln1603His	missense	Exon 37 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152218 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

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: 0.00143

GnomAD2 exomes AF: 0.00405 AC: 1010 AN: 249210 AF XY: 0.00299

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.000811 AC: 1186 AN: 1461640 Hom.: 20 Cov.: 31 AF XY: 0.000685 AC XY: 498 AN XY: 727096

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0258 AC: 1155 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111832

Other (OTH) AF: 0.000480 AC: 29 AN: 60372

GnomAD4 genome AF: 0.00114 AC: 173 AN: 152336 Hom.: 2 Cov.: 33 AF XY: 0.00119 AC XY: 89 AN XY: 74494

African (AFR) AF: 0.0000721 AC: 3 AN: 41588

American (AMR) AF: 0.0109 AC: 167 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000487 Hom.: 1

Bravo AF: 0.00307

ExAC AF: 0.00328 AC: 396

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	20
DANN	Benign	0.67
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.68
PrimateAI	Benign	0.33	T
REVEL	Benign	0.23
Sift4G	Benign	0.39	T
Polyphen		0.0010	B
Vest4		0.21
MutPred		0.16		Gain of catalytic residue at D1602 (P = 0.0809)
MVP		0.89
MPC		0.16
ClinPred		0.018	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.32
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs8178106; hg19: chr8-48794626;