rs8178046

Positions:

• chr8-47929148-G-A
• chr8-47929148-G-T

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.2083C>T​(p.Pro695Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,579,236 control chromosomes in the GnomAD database, including 249 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (18 hom., cov: 32)
  • Exomes 𝑓: 0.015 (231 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.962

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=0.0030925572).
• BP6: Variant 8-47929148-G-A is Benign according to our data. Variant chr8-47929148-G-A is described in ClinVar as [Benign]. Clinvar id is 379426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-47929148-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0112 (1713/152292) while in subpopulation NFE AF= 0.0194 (1323/68024). AF 95% confidence interval is 0.0186. There are 18 homozygotes in gnomad4. There are 767 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.2083C>T	p.Pro695Ser	missense_variant	19/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.2083C>T	p.Pro695Ser	missense_variant	19/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.2083C>T	p.Pro695Ser	missense_variant	19/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.2083C>T	p.Pro695Ser	missense_variant	19/85	1
PRKDC	ENST00000541488.1	n.22C>T		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1717 AN: 152174 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00462

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00980 AC: 1956 AN: 199624 Hom.: 17 AF XY: 0.00918 AC XY: 977 AN XY: 106480

Gnomad AFR exome AF: 0.00352

Gnomad AMR exome AF: 0.00455

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.0000668

Gnomad SAS exome AF: 0.000318

Gnomad FIN exome AF: 0.00584

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0100

GnomAD4 exome AF: 0.0151 AC: 21536 AN: 1426944 Hom.: 231 Cov.: 30 AF XY: 0.0147 AC XY: 10352 AN XY: 706320

Gnomad4 AFR exome AF: 0.00241

Gnomad4 AMR exome AF: 0.00515

Gnomad4 ASJ exome AF: 0.00903

Gnomad4 EAS exome AF: 0.0000519

Gnomad4 SAS exome AF: 0.000504

Gnomad4 FIN exome AF: 0.00587

Gnomad4 NFE exome AF: 0.0183

Gnomad4 OTH exome AF: 0.00997

GnomAD4 genome AF: 0.0112 AC: 1713 AN: 152292 Hom.: 18 Cov.: 32 AF XY: 0.0103 AC XY: 767 AN XY: 74474

Gnomad4 AFR AF: 0.00277

Gnomad4 AMR AF: 0.00752

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00462

Gnomad4 NFE AF: 0.0194

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.0172 Hom.: 68

Bravo AF: 0.0117

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.00329 AC: 12

ESP6500EA AF: 0.0170 AC: 139

ExAC AF: 0.00776 AC: 928

Asia WGS AF: 0.000577 AC: 2 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

Sep 13, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.64
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.031
Sift	Benign	0.33	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.0090	B;B
Vest4		0.079
MVP		0.58
MPC		0.17
ClinPred		0.0042	T
GERP RS		2.2
Varity_R		0.037
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs8178046; hg19: chr8-48841708; COSMIC: COSV104628420;