rs758666662

Variant names:

• chr8-47803383-C-A
• rs758666662
• NM_006904.7:c.9845G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-47803383-C-A
• chr8-47803383-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006904.7(PRKDC):​c.9845G>T​(p.Arg3282Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3282H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.9845G>T	p.Arg3282Leu	missense_variant	Exon 70 of 86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.9845G>T	p.Arg3282Leu	missense_variant	Exon 70 of 85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.9845G>T	p.Arg3282Leu	missense_variant	Exon 70 of 86	1	NM_006904.7	ENSP00000313420.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461706 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727134

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111866

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Oct 07, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with leucine at codon 3282 of the PRKDC protein (p.Arg3282Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PRKDC-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.0084	T
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.5	M;M
PhyloP100		1.6
PrimateAI	Benign	0.25	T
REVEL	Uncertain	0.54
Sift4G	Uncertain	0.027	D;D
Polyphen		0.79	P;.
Vest4		0.65
MutPred		0.73		Loss of MoRF binding (P = 0.0017);Loss of MoRF binding (P = 0.0017);
MVP		0.90
MPC		0.40
ClinPred		0.76	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.16
gMVP		0.47
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: rs758666662; hg19: chr8-48715944;