rs8178232

Positions:

• chr8-47789225-A-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.10684T>A​(p.Leu3562Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,585,258 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (16 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (59 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.727

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=0.005986452).
• BP6: Variant 8-47789225-A-T is Benign according to our data. Variant chr8-47789225-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 440194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00478 (727/151970) while in subpopulation AMR AF= 0.0346 (528/15252). AF 95% confidence interval is 0.0322. There are 16 homozygotes in gnomad4. There are 443 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.10684T>A	p.Leu3562Met	missense_variant	75/86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.10684T>A	p.Leu3562Met	missense_variant	75/85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.10684T>A	p.Leu3562Met	missense_variant	75/86	1	NM_006904.7	ENSP00000313420	P1
PRKDC	ENST00000338368.7	c.10684T>A	p.Leu3562Met	missense_variant	75/85	1		ENSP00000345182
PRKDC	ENST00000697603.1	c.3361T>A	p.Leu1121Met	missense_variant	22/33			ENSP00000513358
PRKDC	ENST00000697602.1	n.1257T>A		non_coding_transcript_exon_variant	7/18

Frequencies

GnomAD3 genomes AF: 0.00479 AC: 727 AN: 151864 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0298

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00746 AC: 1697 AN: 227604 Hom.: 39 AF XY: 0.00594 AC XY: 736 AN XY: 123854

Gnomad AFR exome AF: 0.000335

Gnomad AMR exome AF: 0.0388

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0344

Gnomad SAS exome AF: 0.000395

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000839

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00196 AC: 2813 AN: 1433288 Hom.: 59 Cov.: 31 AF XY: 0.00178 AC XY: 1268 AN XY: 712080

Gnomad4 AFR exome AF: 0.000308

Gnomad4 AMR exome AF: 0.0355

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0305

Gnomad4 SAS exome AF: 0.000687

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000445

Gnomad4 OTH exome AF: 0.00196

GnomAD4 genome AF: 0.00478 AC: 727 AN: 151970 Hom.: 16 Cov.: 33 AF XY: 0.00596 AC XY: 443 AN XY: 74268

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.0346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0301

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00147 Hom.: 3

Bravo AF: 0.00677

ESP6500AA AF: 0.00112 AC: 4

ESP6500EA AF: 0.000246 AC: 2

ExAC AF: 0.00592 AC: 715

Asia WGS AF: 0.0120 AC: 43 AN: 3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2018	- -

Severe combined immunodeficiency due to DNA-PKcs deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0060	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
REVEL	Benign	0.10
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.41
MVP		0.86
MPC		0.68
ClinPred		0.091	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.53

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: rs8178232; hg19: chr8-48701786; COSMIC: COSV58060395;