rs56053523

chr8-47820910-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_006904.7(PRKDC):c.9145C>T(p.Leu3049=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00831 in 1,606,574 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (67 hom.)
• Consequence: PRKDC NM_006904.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.538

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 8-47820910-G-A is Benign according to our data. Variant chr8-47820910-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 380484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-47820910-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.538 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKDC	NM_006904.7	c.9145C>T	p.Leu3049=	synonymous_variant	66/86	ENST00000314191.7
PRKDC	NM_001081640.2	c.9145C>T	p.Leu3049=	synonymous_variant	66/85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKDC	ENST00000314191.7	c.9145C>T	p.Leu3049=	synonymous_variant	66/86	1	NM_006904.7	P1
PRKDC	ENST00000338368.7	c.9145C>T	p.Leu3049=	synonymous_variant	66/85	1
PRKDC	ENST00000697603.1	c.1822C>T	p.Leu608=	synonymous_variant	13/33

Frequencies

GnomAD3 genomes AF: 0.00645 AC: 980 AN: 152046 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00957

Gnomad OTH AF: 0.00528

GnomAD3 exomes AF: 0.00645 AC: 1602 AN: 248532 Hom.: 8 AF XY: 0.00613 AC XY: 827 AN XY: 134894

Gnomad AFR exome AF: 0.00175

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.00807

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000918

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.00887

Gnomad OTH exome AF: 0.00464

GnomAD4 exome AF: 0.00850 AC: 12364 AN: 1454410 Hom.: 67 Cov.: 30 AF XY: 0.00813 AC XY: 5884 AN XY: 723444

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.00902

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000848

Gnomad4 FIN exome AF: 0.0148

Gnomad4 NFE exome AF: 0.00958

Gnomad4 OTH exome AF: 0.00858

GnomAD4 genome AF: 0.00645 AC: 981 AN: 152164 Hom.: 3 Cov.: 32 AF XY: 0.00639 AC XY: 475 AN XY: 74392

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0152

Gnomad4 NFE AF: 0.00959

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00772 Hom.: 5

Bravo AF: 0.00526

Asia WGS AF: 0.00115 AC: 5 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 21, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

PRKDC: BP4, BS2 -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	6.2
Dann	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs56053523; hg19: chr8-48733471; COSMIC: COSV58058155;