NM_006904.7:c.3698C>T

Variant names:

• chr8-47893288-G-A
• rs575674401
• NM_006904.7:c.3698C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006904.7(PRKDC):​c.3698C>T​(p.Ser1233Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000255 in 1,610,456 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.15

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.3698C>T	p.Ser1233Leu	missense_variant	Exon 31 of 86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.3698C>T	p.Ser1233Leu	missense_variant	Exon 31 of 85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.3698C>T	p.Ser1233Leu	missense_variant	Exon 31 of 86	1	NM_006904.7	ENSP00000313420.3
PRKDC	ENST00000338368.7	c.3698C>T	p.Ser1233Leu	missense_variant	Exon 31 of 85	1		ENSP00000345182.4

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000370 AC: 9 AN: 243554 Hom.: 0 AF XY: 0.0000680 AC XY: 9 AN XY: 132286

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000566

Gnomad SAS exome AF: 0.0000334

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000454

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1458218 Hom.: 0 Cov.: 30 AF XY: 0.0000331 AC XY: 24 AN XY: 724996

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74384

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Nov 20, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S1233L variant (also known as c.3698C>T), located in coding exon 31 of the PRKDC gene, results from a C to T substitution at nucleotide position 3698. The serine at codon 1233 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Aug 30, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.21
Sift	Benign	0.069	T;T
Sift4G	Uncertain	0.032	D;D
Polyphen		0.40	B;.
Vest4		0.51
MutPred		0.38		Loss of glycosylation at S1233 (P = 0.0118);Loss of glycosylation at S1233 (P = 0.0118);
MVP		0.69
MPC		0.22
ClinPred		0.15	T
GERP RS		4.9
Varity_R		0.040
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs575674401; hg19: chr8-48805848;