NM_006904.7:c.9145C>G

Variant names:

• chr8-47820910-G-C
• rs56053523
• NM_006904.7:c.9145C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006904.7(PRKDC):​c.9145C>G​(p.Leu3049Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,452 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L3049L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.538
• Publications: 0 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	NM_006904.7	MANE Select	c.9145C>G	p.Leu3049Val	missense	Exon 66 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.9145C>G	p.Leu3049Val	missense	Exon 66 of 85	NP_001075109.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	ENST00000314191.7	TSL:1 MANE Select	c.9145C>G	p.Leu3049Val	missense	Exon 66 of 86	ENSP00000313420.3
	PRKDC	ENST00000338368.7	TSL:1	c.9145C>G	p.Leu3049Val	missense	Exon 66 of 85	ENSP00000345182.4
	PRKDC	ENST00000697603.1		c.1822C>G	p.Leu608Val	missense	Exon 13 of 33	ENSP00000513358.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454452 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 723462

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25936

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 84878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1107300

Other (OTH) AF: 0.00 AC: 0 AN: 59990

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.54
PrimateAI	Uncertain	0.54	T
REVEL	Uncertain	0.40
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.43
MutPred		0.49		Gain of methylation at K3050 (P = 0.0446)
MVP		0.80
MPC		0.36
ClinPred		0.93	D
GERP RS		5.0
Varity_R		0.24
gMVP		0.37
Mutation Taster		=79/21	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: rs56053523; hg19: chr8-48733471;