rs8178208

chr8-47817561-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006904.7(PRKDC):c.9446G>A(p.Gly3149Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 1,576,712 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (55 hom.)
• Consequence: PRKDC NM_006904.7 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.35

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 -16 ACMG points.

• BP6: Variant 8-47817561-C-T is Benign according to our data. Variant chr8-47817561-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 475242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-47817561-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00387 (589/152154) while in subpopulation SAS AF= 0.0251 (121/4820). AF 95% confidence interval is 0.0215. There are 4 homozygotes in gnomad4. There are 299 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.9446G>A	p.Gly3149Asp	missense_variant, splice_region_variant	68/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.9446G>A	p.Gly3149Asp	missense_variant, splice_region_variant	68/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.9446G>A	p.Gly3149Asp	missense_variant, splice_region_variant	68/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.9446G>A	p.Gly3149Asp	missense_variant, splice_region_variant	68/85	1
PRKDC	ENST00000697603.1	c.2123G>A	p.Gly708Asp	missense_variant, splice_region_variant	15/33
PRKDC	ENST00000697607.1	n.978G>A		non_coding_transcript_exon_variant	1/4

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 586 AN: 152036 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0247

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00519 AC: 1114 AN: 214792 Hom.: 12 AF XY: 0.00625 AC XY: 720 AN XY: 115268

Gnomad AFR exome AF: 0.00450

Gnomad AMR exome AF: 0.00297

Gnomad ASJ exome AF: 0.00573

Gnomad EAS exome AF: 0.0000629

Gnomad SAS exome AF: 0.0215

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00308

Gnomad OTH exome AF: 0.00785

GnomAD4 exome AF: 0.00374 AC: 5329 AN: 1424558 Hom.: 55 Cov.: 27 AF XY: 0.00435 AC XY: 3078 AN XY: 707490

Gnomad4 AFR exome AF: 0.00434

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00590

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0248

Gnomad4 FIN exome AF: 0.0000573

Gnomad4 NFE exome AF: 0.00223

Gnomad4 OTH exome AF: 0.00531

GnomAD4 genome AF: 0.00387 AC: 589 AN: 152154 Hom.: 4 Cov.: 32 AF XY: 0.00402 AC XY: 299 AN XY: 74394

Gnomad4 AFR AF: 0.00441

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0251

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00290

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00346 Hom.: 2

Bravo AF: 0.00348

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00467 AC: 17

ESP6500EA AF: 0.00306 AC: 25

ExAC AF: 0.00486 AC: 585

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 01, 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 28, 2024

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.077	T;.
Eigen	Benign	-0.084
Eigen_PC	Benign	0.051
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
REVEL	Benign	0.14
Sift4G	Benign	0.18	T;T
Polyphen		0.029	B;.
Vest4		0.17
MVP		0.47
MPC		0.26
ClinPred		0.012	T
GERP RS		5.7
Varity_R		0.28
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs8178208; hg19: chr8-48730122;