NM_006904.7:c.9217C>T

Variant names:

• chr8-47820838-G-A
• rs55644332
• NM_006904.7:c.9217C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006904.7(PRKDC):​c.9217C>T​(p.Leu3073Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000543 in 1,613,354 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L3073L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.48
• Publications: 5 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069336295).
• BP6: Variant 8-47820838-G-A is Benign according to our data. Variant chr8-47820838-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 507237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	NM_006904.7	MANE Select	c.9217C>T	p.Leu3073Phe	missense	Exon 66 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.9217C>T	p.Leu3073Phe	missense	Exon 66 of 85	NP_001075109.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	ENST00000314191.7	TSL:1 MANE Select	c.9217C>T	p.Leu3073Phe	missense	Exon 66 of 86	ENSP00000313420.3
	PRKDC	ENST00000338368.7	TSL:1	c.9217C>T	p.Leu3073Phe	missense	Exon 66 of 85	ENSP00000345182.4
	PRKDC	ENST00000697603.1		c.1894C>T	p.Leu632Phe	missense	Exon 13 of 33	ENSP00000513358.1

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 407 AN: 152018 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00947

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000738 AC: 184 AN: 249276 AF XY: 0.000436

Gnomad AFR exome AF: 0.00969

Gnomad AMR exome AF: 0.000637

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000320 AC: 468 AN: 1461218 Hom.: 2 Cov.: 30 AF XY: 0.000270 AC XY: 196 AN XY: 726912

African (AFR) AF: 0.0108 AC: 362 AN: 33472

American (AMR) AF: 0.000648 AC: 29 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111512

Other (OTH) AF: 0.000828 AC: 50 AN: 60352

GnomAD4 genome AF: 0.00268 AC: 408 AN: 152136 Hom.: 2 Cov.: 32 AF XY: 0.00239 AC XY: 178 AN XY: 74382

African (AFR) AF: 0.00947 AC: 393 AN: 41518

American (AMR) AF: 0.000852 AC: 13 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00186 Hom.: 3

Bravo AF: 0.00292

ESP6500AA AF: 0.00990 AC: 38

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000927 AC: 112

Asia WGS AF: 0.000578 AC: 2 AN: 3474

EpiCase AF: 0.0000548

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

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	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.078	T
Eigen	Benign	0.10
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.5
PrimateAI	Benign	0.38	T
REVEL	Benign	0.13
Sift4G	Uncertain	0.031	D
Polyphen		0.98	D
Vest4		0.20
MVP		0.67
MPC		0.38
ClinPred		0.020	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.091
gMVP		0.085
Mutation Taster		=99/1	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: rs55644332; hg19: chr8-48733399; COSMIC: COSV104628813;