rs8178216

Positions:

• chr8-47807283-G-A
• chr8-47807283-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006904.7(PRKDC):​c.9601C>T​(p.Pro3201Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00962 in 1,605,872 control chromosomes in the GnomAD database, including 92 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P3201P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0071 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (89 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.419

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005528927).
• BP6: Variant 8-47807283-G-A is Benign according to our data. Variant chr8-47807283-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 379755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-47807283-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.9601C>T	p.Pro3201Ser	missense_variant	69/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.9601C>T	p.Pro3201Ser	missense_variant	69/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.9601C>T	p.Pro3201Ser	missense_variant	69/86	1	NM_006904.7	P1

Frequencies

GnomAD3 genomes AF: 0.00710 AC: 1080 AN: 152126 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00647 AC: 1575 AN: 243262 Hom.: 11 AF XY: 0.00652 AC XY: 861 AN XY: 132042

Gnomad AFR exome AF: 0.00249

Gnomad AMR exome AF: 0.00196

Gnomad ASJ exome AF: 0.000508

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00249

Gnomad FIN exome AF: 0.00975

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00989 AC: 14370 AN: 1453628 Hom.: 89 Cov.: 30 AF XY: 0.00954 AC XY: 6897 AN XY: 722662

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00173

Gnomad4 ASJ exome AF: 0.000425

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00248

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.0118

Gnomad4 OTH exome AF: 0.00648

GnomAD4 genome AF: 0.00709 AC: 1080 AN: 152244 Hom.: 3 Cov.: 32 AF XY: 0.00690 AC XY: 514 AN XY: 74442

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.0118

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00855 Hom.: 9

Bravo AF: 0.00588

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00107 AC: 4

ESP6500EA AF: 0.0136 AC: 112

ExAC AF: 0.00667 AC: 806

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2022	Variant summary: PRKDC c.9598C>T (p.Pro3200Ser) (refseq HGVS c.9601C>T, p.Pro3201Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0065 in 243262 control chromosomes in the gnomAD database, including 11 homozygotes. The observed variant frequency is approximately 18 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRKDC causing Severe Combined Immunodeficiency phenotype (0.00035), strongly suggesting that the variant is benign. To our knowledge, no penetrant association or occurrence of c.9598C>T in individuals affected with Severe Combined Immunodeficiency (specifically Immunodeficiency 26, with or without neurologic abnormalities, OMIM 60089) and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2018	This variant is associated with the following publications: (PMID: 24476948) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	PRKDC: BP4, BS1, BS2 -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.24
DANN	Benign	0.51
DEOGEN2	Benign	0.042	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.58	T;T
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
REVEL	Benign	0.072
Sift4G	Benign	0.56	T;T
Polyphen		0.0030	B;.
Vest4		0.035
MVP		0.41
MPC		0.17
ClinPred		0.00098	T
GERP RS		-2.2
Varity_R		0.023
gMVP		0.087

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: rs8178216; hg19: chr8-48719844; COSMIC: COSV58042942; COSMIC: COSV58042942;