rs575674401

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr8-47893288-G-A
• chr8-47893288-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/21 in silico tools predict a benign 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. S1233W) has been classified 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

Our verdict: Uncertain_significance. The variant received 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

GnomAD2 exomes AF: 0.0000370 AC: 9 AN: 243554 AF XY: 0.0000680

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 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 AC: 5 AN: 33418

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44354

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26054

Gnomad4 EAS exome AF: 0.0000253 AC: 1 AN: 39600

Gnomad4 SAS exome AF: 0.0000233 AC: 2 AN: 85760

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53220

Gnomad4 NFE exome AF: 0.0000207 AC: 23 AN: 1109824

Gnomad4 Remaining exome AF: 0.0000332 AC: 2 AN: 60226

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 AC: 0.0000241208 AN: 0.0000241208

Gnomad4 AMR AF: 0.0000654 AC: 0.0000653937 AN: 0.0000653937

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000882 AC: 0.0000881886 AN: 0.0000881886

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

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

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3698C>T (p.S1233L) alteration is located in exon 31 (coding exon 31) of the PRKDC gene. This alteration results from a C to T substitution at nucleotide position 3698, causing the serine (S) at amino acid position 1233 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, 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
Mutation Taster		=90/10	polymorphism

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;