rs754453280

Positions:

• chr8-47960110-G-A
• chr8-47960110-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006904.7(PRKDC):​c.17C>T​(p.Ala6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000886 in 1,354,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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. A6S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.332

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061723173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.17C>T	p.Ala6Val	missense_variant	1/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.17C>T	p.Ala6Val	missense_variant	1/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.17C>T	p.Ala6Val	missense_variant	1/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.17C>T	p.Ala6Val	missense_variant	1/85	1
PRKDC	ENST00000697591.1	n.58C>T		non_coding_transcript_exon_variant	1/15

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000886 AC: 12 AN: 1354662 Hom.: 0 Cov.: 31 AF XY: 0.00000901 AC XY: 6 AN XY: 665954

Gnomad4 AFR exome AF: 0.0000350

Gnomad4 AMR exome AF: 0.0000882

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000389

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000376

Gnomad4 OTH exome AF: 0.0000177

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000158 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2021

The p.A6V variant (also known as c.17C>T), located in coding exon 1 of the PRKDC gene, results from a C to T substitution at nucleotide position 17. The alanine at codon 6 is replaced by valine, an amino acid with similar 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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 05, 2022

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. ClinVar contains an entry for this variant (Variation ID: 571987). This variant has not been reported in the literature in individuals affected with PRKDC-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 6 of the PRKDC protein (p.Ala6Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.036
Sift	Benign	0.030	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		0.22	B;B
Vest4		0.084
MutPred		0.15		Loss of disorder (P = 0.0435);Loss of disorder (P = 0.0435);
MVP		0.24
MPC		0.24
ClinPred		0.37	T
GERP RS		-1.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.040
gMVP		0.24

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: rs754453280; hg19: chr8-48872670;