rs4521758

Variant names:

• chr8-47829009-C-T
• rs4521758
• NM_006904.7:c.8398-662G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006904.7(PRKDC):​c.8398-662G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 152,112 control chromosomes in the GnomAD database, including 8,339 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (8339 hom., cov: 33)
• Consequence: PRKDC NM_006904.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.975
• Publications: 12 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.8398-662G>A		intron_variant	Intron 61 of 85	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.8398-662G>A		intron_variant	Intron 61 of 84		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.8398-662G>A		intron_variant	Intron 61 of 85	1	NM_006904.7	ENSP00000313420.3
PRKDC	ENST00000338368.7	c.8398-662G>A		intron_variant	Intron 61 of 84	1		ENSP00000345182.4
PRKDC	ENST00000697603.1	c.1075-662G>A		intron_variant	Intron 8 of 32			ENSP00000513358.1
PRKDC	ENST00000697608.1	n.917-662G>A		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39660 AN: 151994 Hom.: 8323 Cov.: 33

Gnomad AFR AF: 0.576

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.0916

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.259

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.261 AC: 39737 AN: 152112 Hom.: 8339 Cov.: 33 AF XY: 0.258 AC XY: 19202 AN XY: 74370

African (AFR) AF: 0.577 AC: 23903 AN: 41458

American (AMR) AF: 0.284 AC: 4345 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 726 AN: 3468

East Asian (EAS) AF: 0.162 AC: 842 AN: 5182

South Asian (SAS) AF: 0.210 AC: 1016 AN: 4828

European-Finnish (FIN) AF: 0.0916 AC: 969 AN: 10580

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7160 AN: 68000

Other (OTH) AF: 0.259 AC: 548 AN: 2112

Alfa AF: 0.161 Hom.: 5342

Bravo AF: 0.294

Asia WGS AF: 0.223 AC: 774 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.84
DANN	Benign	0.49
PhyloP100		-0.97
Mutation Taster		=100/0	polymorphism (auto)

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: rs4521758; hg19: chr8-48741570;