chr8-47893288-G-C

Variant names:

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

Variant summary

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

The NM_006904.7(PRKDC):​c.3698C>G​(p.Ser1233Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,458,218 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 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. S1233L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.15
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.3698C>G	p.Ser1233Trp	missense_variant	Exon 31 of 86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.3698C>G	p.Ser1233Trp	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>G	p.Ser1233Trp	missense_variant	Exon 31 of 86	1	NM_006904.7	ENSP00000313420.3
PRKDC	ENST00000338368.7	c.3698C>G	p.Ser1233Trp	missense_variant	Exon 31 of 85	1		ENSP00000345182.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458218 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724996

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 85760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109824

Other (OTH) AF: 0.0000166 AC: 1 AN: 60226

GnomAD4 genome Cov.: 33

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 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with PRKDC-related conditions. ClinVar contains an entry for this variant (Variation ID: 1380012). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine with tryptophan at codon 1233 of the PRKDC protein (p.Ser1233Trp). The serine residue is moderately conserved and there is a large physicochemical difference between serine and tryptophan. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.71	T
PhyloP100		4.1
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.99	D;.
Vest4		0.61
MutPred		0.39		Loss of disorder (P = 0.0038);Loss of disorder (P = 0.0038);
MVP		0.74
MPC		0.76
ClinPred		0.76	D
GERP RS		4.9
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Varity_R		0.053
gMVP		0.54
Mutation Taster		=83/17	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

Other links and lift over

dbSNP: rs575674401; hg19: chr8-48805848;