8-47890319-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_006904.7(PRKDC):c.4009G>A(p.Val1337Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,613,286 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1337A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.657

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011308938).
• BP6: Variant 8-47890319-C-T is Benign according to our data. Variant chr8-47890319-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542005.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chr8-47890319-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.4009G>A	p.Val1337Ile	missense_variant	32/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.4009G>A	p.Val1337Ile	missense_variant	32/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.4009G>A	p.Val1337Ile	missense_variant	32/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.4009G>A	p.Val1337Ile	missense_variant	32/85	1

Frequencies

GnomAD3 genomes AF: 0.000966 AC: 147 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

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: 0.00148

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00104 AC: 258 AN: 248958 Hom.: 1 AF XY: 0.00104 AC XY: 140 AN XY: 135062

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00169 AC: 2473 AN: 1461070 Hom.: 3 Cov.: 30 AF XY: 0.00157 AC XY: 1142 AN XY: 726776

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00207

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.000966 AC: 147 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000968 AC XY: 72 AN XY: 74402

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00149

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000781 Hom.: 0

Bravo AF: 0.00117

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000256 AC: 1

ESP6500EA AF: 0.00181 AC: 15

ExAC AF: 0.000893 AC: 108

EpiCase AF: 0.00207

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jun 16, 2017	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.15
Dann	Benign	0.71
DEOGEN2	Benign	0.073	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.17	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.33	N;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	B;.
Vest4		0.17
MVP		0.38
MPC		0.14
ClinPred		0.016	T
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.12

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: rs56080897; hg19: chr8-48802880; COSMIC: COSV104628606;