rs7830743

chr8-47798394-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006904.7(PRKDC):c.10301T>C(p.Ile3434Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0775 in 1,593,232 control chromosomes in the GnomAD database, including 8,905 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2189 hom., cov: 32)
  • Exomes 𝑓: 0.072 (6716 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.231

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=0.0017988086).
• BP6: Variant 8-47798394-A-G is Benign according to our data. Variant chr8-47798394-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 379415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.10301T>C	p.Ile3434Thr	missense_variant	73/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.10301T>C	p.Ile3434Thr	missense_variant	73/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.10301T>C	p.Ile3434Thr	missense_variant	73/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.10301T>C	p.Ile3434Thr	missense_variant	73/85	1
PRKDC	ENST00000697603.1	c.2978T>C	p.Ile993Thr	missense_variant	20/33
PRKDC	ENST00000697602.1	n.874T>C		non_coding_transcript_exon_variant	5/18

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20257 AN: 152122 Hom.: 2188 Cov.: 32

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.0910

Gnomad EAS AF: 0.0838

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.0322

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0496

Gnomad OTH AF: 0.135

GnomAD3 exomes AF: 0.119 AC: 27068 AN: 226646 Hom.: 3007 AF XY: 0.112 AC XY: 13704 AN XY: 122680

Gnomad AFR exome AF: 0.281

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.0935

Gnomad EAS exome AF: 0.0689

Gnomad SAS exome AF: 0.165

Gnomad FIN exome AF: 0.0388

Gnomad NFE exome AF: 0.0542

Gnomad OTH exome AF: 0.0990

GnomAD4 exome AF: 0.0716 AC: 103208 AN: 1440992 Hom.: 6716 Cov.: 31 AF XY: 0.0728 AC XY: 52116 AN XY: 715512

Gnomad4 AFR exome AF: 0.289

Gnomad4 AMR exome AF: 0.306

Gnomad4 ASJ exome AF: 0.0923

Gnomad4 EAS exome AF: 0.0884

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.0387

Gnomad4 NFE exome AF: 0.0500

Gnomad4 OTH exome AF: 0.0861

GnomAD4 genome AF: 0.133 AC: 20284 AN: 152240 Hom.: 2189 Cov.: 32 AF XY: 0.133 AC XY: 9914 AN XY: 74450

Gnomad4 AFR AF: 0.272

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.0910

Gnomad4 EAS AF: 0.0840

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.0322

Gnomad4 NFE AF: 0.0496

Gnomad4 OTH AF: 0.137

Alfa AF: 0.0776 Hom.: 1334

Bravo AF: 0.158

TwinsUK AF: 0.0520 AC: 193

ALSPAC AF: 0.0496 AC: 191

ESP6500AA AF: 0.261 AC: 975

ESP6500EA AF: 0.0568 AC: 467

ExAC AF: 0.115 AC: 13833

Asia WGS AF: 0.144 AC: 501 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 42% of patients studied by a panel of primary immunodeficiencies. Number of patients: 40. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.042
Dann	Benign	0.23
DEOGEN2	Benign	0.040	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.34	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.40	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.27	T
REVEL	Benign	0.075
Sift4G	Benign	0.50	T;T
Polyphen		0.0	B;.
Vest4		0.0070
MPC		0.21
ClinPred		0.0021	T
GERP RS		-7.7
Varity_R		0.039
gMVP		0.048

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs7830743; hg19: chr8-48710955; COSMIC: COSV58047120;