rs375706148

Variant names:

• chr8-47849499-A-G
• rs375706148
• NM_006904.7:c.7010T>C

Your query was ambiguous. Multiple possible variants found:

• chr8-47849499-A-G
• chr8-47849499-A-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006904.7(PRKDC):​c.7010T>C​(p.Leu2337Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000808 in 1,609,512 control chromosomes in the GnomAD database, including 2 homozygotes. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L2337L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000080 (2 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.08
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.7010T>C	p.Leu2337Pro	missense	Exon 53 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.7010T>C	p.Leu2337Pro	missense	Exon 53 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.7010T>C	p.Leu2337Pro	missense	Exon 53 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.7010T>C	p.Leu2337Pro	missense	Exon 53 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.7010T>C	p.Leu2337Pro	missense	Exon 53 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes AF: 0.0000919 AC: 14 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000820 AC: 20 AN: 243940 AF XY: 0.0000982

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.000620

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000449

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000796 AC: 116 AN: 1457132 Hom.: 2 Cov.: 30 AF XY: 0.0000773 AC XY: 56 AN XY: 724700

African (AFR) AF: 0.000392 AC: 13 AN: 33158

American (AMR) AF: 0.000162 AC: 7 AN: 43322

Ashkenazi Jewish (ASJ) AF: 0.000503 AC: 13 AN: 25858

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.000698 AC: 4 AN: 5734

European-Non Finnish (NFE) AF: 0.0000594 AC: 66 AN: 1110728

Other (OTH) AF: 0.000183 AC: 11 AN: 60190

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152380 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74512

African (AFR) AF: 0.000216 AC: 9 AN: 41590

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000662 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Severe combined immunodeficiency due to DNA-PKcs deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Benign	0.68
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0096	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.1
PrimateAI	Benign	0.42	T
REVEL	Uncertain	0.37
Sift4G	Benign	0.12	T
Polyphen		0.027	B
Vest4		0.70
MVP		0.83
MPC		0.33
ClinPred		0.029	T
GERP RS		3.9
Varity_R		0.19
gMVP		0.65
Mutation Taster		=75/25	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: rs375706148; hg19: chr8-48762060;