rs376211703

chr8-47852777-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_006904.7(PRKDC):c.6901C>G(p.Gln2301Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000837 in 1,557,534 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00088 (3 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.26

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03317797).
• BP6: Variant 8-47852777-G-C is Benign according to our data. Variant chr8-47852777-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542001.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr8-47852777-G-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.6901C>G	p.Gln2301Glu	missense_variant	52/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.6901C>G	p.Gln2301Glu	missense_variant	52/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.6901C>G	p.Gln2301Glu	missense_variant	52/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.6901C>G	p.Gln2301Glu	missense_variant	52/85	1

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000359 AC: 63 AN: 175252 Hom.: 1 AF XY: 0.000388 AC XY: 36 AN XY: 92778

Gnomad AFR exome AF: 0.000285

Gnomad AMR exome AF: 0.0000771

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000251

Gnomad NFE exome AF: 0.000732

Gnomad OTH exome AF: 0.000209

GnomAD4 exome AF: 0.000877 AC: 1232 AN: 1405246 Hom.: 3 Cov.: 27 AF XY: 0.000855 AC XY: 594 AN XY: 694880

Gnomad4 AFR exome AF: 0.000185

Gnomad4 AMR exome AF: 0.0000804

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.000227

Gnomad4 NFE exome AF: 0.00108

Gnomad4 OTH exome AF: 0.000840

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74454

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000671 Hom.: 1

Bravo AF: 0.000514

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000855 AC: 7

ExAC AF: 0.000178 AC: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	PRKDC NM_006904.6 exon 52 p.Gln2301Glu (c.6901C>G): This variant has not been reported in the literature but is present in 63/85696 European alleles, including 1 homozygote, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs376211703). This variant Glutamic Acid (Glu) is present in >15 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	13
Dann	Uncertain	0.98
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.30	T
REVEL	Benign	0.24
Sift4G	Benign	0.36	T;T
Polyphen		0.0010	B;.
Vest4		0.18
MVP		0.66
MPC		0.18
ClinPred		0.013	T
GERP RS		0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs376211703; hg19: chr8-48765338; COSMIC: COSV104628581;