8-47954424-G-T

Position:

• chr8-47954424-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006904.7(PRKDC):​c.422C>A​(p.Ser141Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000501 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: 0.0000050 (0 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.57

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30085412).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.422C>A	p.Ser141Tyr	missense_variant	5/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.422C>A	p.Ser141Tyr	missense_variant	5/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.422C>A	p.Ser141Tyr	missense_variant	5/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.422C>A	p.Ser141Tyr	missense_variant	5/85	1
PRKDC	ENST00000540819.1	c.137C>A	p.Ser46Tyr	missense_variant	5/5	3
PRKDC	ENST00000697591.1	n.463C>A		non_coding_transcript_exon_variant	5/15

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000770 AC: 1 AN: 129850 Hom.: 0 AF XY: 0.0000145 AC XY: 1 AN XY: 68798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000501 AC: 6 AN: 1197652 Hom.: 0 Cov.: 20 AF XY: 0.00000678 AC XY: 4 AN XY: 590096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000172

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000538

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Uncertain	-0.11	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.67
MutPred		0.35		Loss of phosphorylation at S141 (P = 0.0477);Loss of phosphorylation at S141 (P = 0.0477);.;
MVP		0.64
MPC		0.74
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.30
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs201231274; hg19: chr8-48866984;