rs8178040

Positions:

• chr8-47929865-T-C

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.2040A>G​(p.Ile680Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,598,176 control chromosomes in the GnomAD database, including 60 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 0.010 (29 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (31 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.497

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=0.003422469).
• BP6: Variant 8-47929865-T-C is Benign according to our data. Variant chr8-47929865-T-C is described in ClinVar as [Benign]. Clinvar id is 377114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1576/152342) while in subpopulation AFR AF= 0.0368 (1530/41578). AF 95% confidence interval is 0.0353. There are 29 homozygotes in gnomad4. There are 734 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.2040A>G	p.Ile680Met	missense_variant	18/86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.2040A>G	p.Ile680Met	missense_variant	18/85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.2040A>G	p.Ile680Met	missense_variant	18/86	1	NM_006904.7	ENSP00000313420	P1
PRKDC	ENST00000338368.7	c.2040A>G	p.Ile680Met	missense_variant	18/85	1		ENSP00000345182

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1562 AN: 152224 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0366

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00248 AC: 580 AN: 233842 Hom.: 9 AF XY: 0.00188 AC XY: 238 AN XY: 126742

Gnomad AFR exome AF: 0.0352

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000383

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000275

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.000942 AC: 1362 AN: 1445834 Hom.: 31 Cov.: 31 AF XY: 0.000807 AC XY: 580 AN XY: 718486

Gnomad4 AFR exome AF: 0.0355

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.0103 AC: 1576 AN: 152342 Hom.: 29 Cov.: 32 AF XY: 0.00985 AC XY: 734 AN XY: 74502

Gnomad4 AFR AF: 0.0368

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00211 Hom.: 11

Bravo AF: 0.0113

ESP6500AA AF: 0.0386 AC: 140

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.00328 AC: 396

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000548

EpiControl AF: 0.0000596

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.70
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.66
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.89	N;N
REVEL	Benign	0.051
Sift	Benign	0.25	T;T
Sift4G	Benign	0.077	T;T
Polyphen		0.027	B;B
Vest4		0.14
MVP		0.27
MPC		0.22
ClinPred		0.010	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs8178040; hg19: chr8-48842425; COSMIC: COSV58047078; COSMIC: COSV58047078;