Genetic Variant PRKDC:p.Leu2337Gln (chr8-47849499-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006904.7(PRKDC):c.7010T>A(p.Leu2337Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000618 in 1,457,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. L2337P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PRKDC
NM_006904.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.08

Publications

0 publications found

Variant links:

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

PRKDC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7 link	c.7010T>A	p.Leu2337Gln	missense_variant	Exon 53 of 86	ENST00000314191.7	NP_008835.5	P78527-1
PRKDC	NM_001081640.2 link	c.7010T>A	p.Leu2337Gln	missense_variant	Exon 53 of 85		NP_001075109.1	P78527-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7 link	c.7010T>A	p.Leu2337Gln	missense_variant	Exon 53 of 86	1	NM_006904.7	ENSP00000313420.3		P78527-1
PRKDC	ENST00000338368.7 link	c.7010T>A	p.Leu2337Gln	missense_variant	Exon 53 of 85	1		ENSP00000345182.4		P78527-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000618

AC:

AN:

1457132

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

724700

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33158

American (AMR)

AF:

0.00

AC:

AN:

43322

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25858

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

85140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00000810

AC:

AN:

1110728

Other (OTH)

AF:

0.00

AC:

AN:

60190

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

3.1

PrimateAI

Benign

0.36

REVEL

Benign

0.16

Sift4G

Benign

0.078

T;T

Polyphen

0.41

B;.

Vest4

0.26

MutPred

0.38

Gain of disorder (P = 0.0223);Gain of disorder (P = 0.0223);

MVP

0.66

MPC

0.22

ClinPred

0.24

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.24

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.36

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.36

Position offset: -2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over