NM_006904.7:c.10684T>A

Variant names:

• chr8-47789225-A-T
• rs8178232
• NM_006904.7:c.10684T>A

Variant summary

Our verdict is Benign. The variant received -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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L3562F) has been classified as Uncertain significance.

• 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
• Publications: 12 publications found

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]

PRKDC Gene-Disease associations (from GenCC):

• severe combined immunodeficiency due to DNA-PKcs deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006904.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	NM_006904.7	MANE Select	c.10684T>A	p.Leu3562Met	missense	Exon 75 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.10684T>A	p.Leu3562Met	missense	Exon 75 of 85	NP_001075109.1	P78527-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	ENST00000314191.7	TSL:1 MANE Select	c.10684T>A	p.Leu3562Met	missense	Exon 75 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.10684T>A	p.Leu3562Met	missense	Exon 75 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.10693T>A	p.Leu3565Met	missense	Exon 75 of 86	ENSP00000581783.1

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

GnomAD2 exomes AF: 0.00746 AC: 1697 AN: 227604 AF XY: 0.00594

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 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

African (AFR) AF: 0.000308 AC: 10 AN: 32432

American (AMR) AF: 0.0355 AC: 1382 AN: 38914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.0305 AC: 1200 AN: 39320

South Asian (SAS) AF: 0.000687 AC: 54 AN: 78590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52578

Middle Eastern (MID) AF: 0.000360 AC: 2 AN: 5550

European-Non Finnish (NFE) AF: 0.0000445 AC: 49 AN: 1101630

Other (OTH) AF: 0.00196 AC: 116 AN: 59104

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

African (AFR) AF: 0.000458 AC: 19 AN: 41522

American (AMR) AF: 0.0346 AC: 528 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0301 AC: 156 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67936

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Severe combined immunodeficiency due to DNA-PKcs deficiency (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.73
PrimateAI	Uncertain	0.50	T
REVEL	Benign	0.10
Sift4G	Pathogenic	0.0	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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

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