rs374403400

Variant names:

• chr8-47849230-G-A
• rs374403400
• NM_006904.7:c.7204C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006904.7(PRKDC):​c.7204C>T​(p.Leu2402Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000827 in 1,613,960 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L2402L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (2 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.48
• Publications: 3 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015803784).
• BP6: Variant 8-47849230-G-A is Benign according to our data. Variant chr8-47849230-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 440192.
• 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.7204C>T	p.Leu2402Phe	missense	Exon 54 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.7204C>T	p.Leu2402Phe	missense	Exon 54 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.7204C>T	p.Leu2402Phe	missense	Exon 54 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.7204C>T	p.Leu2402Phe	missense	Exon 54 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.7204C>T	p.Leu2402Phe	missense	Exon 54 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000602 AC: 150 AN: 249276 AF XY: 0.000666

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000789

Gnomad NFE exome AF: 0.000681

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000858 AC: 1254 AN: 1461710 Hom.: 2 Cov.: 31 AF XY: 0.000861 AC XY: 626 AN XY: 727138

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00137 AC: 118 AN: 86258

European-Finnish (FIN) AF: 0.00101 AC: 54 AN: 53402

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000925 AC: 1028 AN: 1111868

Other (OTH) AF: 0.000729 AC: 44 AN: 60374

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000604 AC XY: 45 AN XY: 74442

African (AFR) AF: 0.000169 AC: 7 AN: 41534

American (AMR) AF: 0.000261 AC: 4 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000803 Hom.: 0

Bravo AF: 0.000491

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000602 AC: 5

ExAC AF: 0.000637 AC: 77

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	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	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.5
PrimateAI	Benign	0.47	T
REVEL	Benign	0.14
Sift4G	Uncertain	0.022	D
Polyphen		0.96	P
Vest4		0.30
MVP		0.55
MPC		0.24
ClinPred		0.034	T
GERP RS		3.9
Varity_R		0.091
gMVP		0.30
Mutation Taster		=71/29	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: rs374403400; hg19: chr8-48761791;