chr8-47954424-G-A

Variant names:

• chr8-47954424-G-A
• rs201231274
• NM_006904.7:c.422C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006904.7(PRKDC):​c.422C>T​(p.Ser141Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000835 in 1,197,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S141C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.57
• 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30152115).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	NM_006904.7	MANE Select	c.422C>T	p.Ser141Phe	missense	Exon 5 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.422C>T	p.Ser141Phe	missense	Exon 5 of 85	NP_001075109.1	P78527-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	ENST00000314191.7	TSL:1 MANE Select	c.422C>T	p.Ser141Phe	missense	Exon 5 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.422C>T	p.Ser141Phe	missense	Exon 5 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.422C>T	p.Ser141Phe	missense	Exon 5 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.35e-7 AC: 1 AN: 1197652 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 590096

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26434

American (AMR) AF: 0.00 AC: 0 AN: 27052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21844

East Asian (EAS) AF: 0.00 AC: 0 AN: 33400

South Asian (SAS) AF: 0.00 AC: 0 AN: 58034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5094

European-Non Finnish (NFE) AF: 0.00000108 AC: 1 AN: 929462

Other (OTH) AF: 0.00 AC: 0 AN: 49838

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	-0.020	T
PhyloP100		5.6
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.68
MutPred		0.36		Loss of phosphorylation at S141 (P = 0.037)
MVP		0.61
MPC		0.66
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.33
gMVP		0.34
Mutation Taster		=72/28	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: rs201231274; hg19: chr8-48866984;