rs8178106

Positions:

• chr8-47882065-C-A

Variant summary

Our verdict is Benign. Variant got -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. 13/17 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:2
• Conservation: PhyloP100: 0.678

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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. gnomad4_exome 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 gnomad4_exome. There are 498 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.4809G>T	p.Gln1603His	missense_variant	37/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.4809G>T	p.Gln1603His	missense_variant	37/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.4809G>T	p.Gln1603His	missense_variant	37/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.4809G>T	p.Gln1603His	missense_variant	37/85	1
PRKDC	ENST00000697611.1	n.913G>T		non_coding_transcript_exon_variant	1/2

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

GnomAD3 exomes AF: 0.00405 AC: 1010 AN: 249210 Hom.: 17 AF XY: 0.00299 AC XY: 404 AN XY: 135204

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 SAS 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

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0258

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000480

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

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000186 Hom.: 0

Bravo AF: 0.00307

ExAC AF: 0.00328 AC: 396

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2017

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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;D
MetaRNN	Benign	0.0087	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.64	N;N
PrimateAI	Benign	0.33	T
REVEL	Benign	0.23
Sift4G	Benign	0.39	T;T
Polyphen		0.0010	B;.
Vest4		0.21
MutPred		0.16		Gain of catalytic residue at D1602 (P = 0.0809);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs8178106; hg19: chr8-48794626;