8-47778614-G-C

Variant names:

• chr8-47778614-G-C
• rs201214138
• NM_006904.7:c.11698C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006904.7(PRKDC):​c.11698C>G​(p.Leu3900Val) variant causes a missense change. The variant allele was found at a frequency of 0.000764 in 1,613,794 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L3900L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00057 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (1 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 4.66
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22651342).

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.11698C>G	p.Leu3900Val	missense	Exon 83 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.11605C>G	p.Leu3869Val	missense	Exon 82 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.11698C>G	p.Leu3900Val	missense	Exon 83 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.11605C>G	p.Leu3869Val	missense	Exon 82 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.11707C>G	p.Leu3903Val	missense	Exon 83 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes AF: 0.000571 AC: 87 AN: 152244 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000608 AC: 151 AN: 248328 AF XY: 0.000601

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000784 AC: 1146 AN: 1461432 Hom.: 1 Cov.: 31 AF XY: 0.000780 AC XY: 567 AN XY: 726984

African (AFR) AF: 0.000269 AC: 9 AN: 33478

American (AMR) AF: 0.000291 AC: 13 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.000996 AC: 26 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86194

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53388

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.000902 AC: 1003 AN: 1111754

Other (OTH) AF: 0.00106 AC: 64 AN: 60370

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152362 Hom.: 1 Cov.: 32 AF XY: 0.000671 AC XY: 50 AN XY: 74502

African (AFR) AF: 0.000168 AC: 7 AN: 41584

American (AMR) AF: 0.000588 AC: 9 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68040

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000540

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000250 AC: 1

ESP6500EA AF: 0.000841 AC: 7

ExAC AF: 0.000662 AC: 80

EpiCase AF: 0.00164

EpiControl AF: 0.00137

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	2	-	Severe combined immunodeficiency due to DNA-PKcs deficiency (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	2.0	M
PhyloP100		4.7
PrimateAI	Uncertain	0.56	T
REVEL	Uncertain	0.51
Sift4G	Uncertain	0.0090	D
Polyphen		0.97	D
Vest4		0.68
MVP		0.63
MPC		0.69
ClinPred		0.18	T
GERP RS		5.5
PromoterAI		-0.021	Neutral
Varity_R		0.38
gMVP		0.72
Mutation Taster		=78/22	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: rs201214138; hg19: chr8-48691175; COSMIC: COSV104628636;