chr8-47885946-T-C

Variant names:

• chr8-47885946-T-C
• rs368553930
• NM_006904.7:c.4774A>G
• PRKDC p.Met1592Val

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_006904.7(PRKDC):​c.4774A>G​(p.Met1592Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000616 in 1,610,982 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (1 hom.)
• Consequence: PRKDC NM_006904.7 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.95
• 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, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3200339).

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.4774A>G	p.Met1592Val	missense splice_region	Exon 36 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.4774A>G	p.Met1592Val	missense splice_region	Exon 36 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.4774A>G	p.Met1592Val	missense splice_region	Exon 36 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.4774A>G	p.Met1592Val	missense splice_region	Exon 36 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.4774A>G	p.Met1592Val	missense splice_region	Exon 36 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000266 AC: 66 AN: 248250 AF XY: 0.000341

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000471

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000632 AC: 922 AN: 1458698 Hom.: 1 Cov.: 30 AF XY: 0.000623 AC XY: 452 AN XY: 725812

African (AFR) AF: 0.00 AC: 0 AN: 33358

American (AMR) AF: 0.000179 AC: 8 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86098

European-Finnish (FIN) AF: 0.000188 AC: 10 AN: 53254

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.000779 AC: 864 AN: 1109542

Other (OTH) AF: 0.000647 AC: 39 AN: 60278

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74462

African (AFR) AF: 0.000144 AC: 6 AN: 41572

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000422 Hom.: 0

Bravo AF: 0.000382

EpiCase AF: 0.000654

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Severe combined immunodeficiency due to DNA-PKcs deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.0
PrimateAI	Uncertain	0.49	T
REVEL	Benign	0.22
Sift4G	Uncertain	0.016	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.54
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs368553930;

hg19: chr8-48798507;

COSMIC: COSV58049741;