rs762000221

Variant names:

• chr8-47778599-C-A
• rs762000221
• NM_006904.7:c.11713G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-47778599-C-A
• chr8-47778599-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_006904.7(PRKDC):​c.11713G>T​(p.Ala3905Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,360 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3905V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (1 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.803
• Publications: 2 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34199056).

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.11713G>T	p.Ala3905Ser	missense	Exon 83 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.11620G>T	p.Ala3874Ser	missense	Exon 82 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.11713G>T	p.Ala3905Ser	missense	Exon 83 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.11620G>T	p.Ala3874Ser	missense	Exon 82 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.11722G>T	p.Ala3908Ser	missense	Exon 83 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461360 Hom.: 1 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726928

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111720

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.13
BayesDel_addAF	Benign	0.0082	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.80
PrimateAI	Benign	0.30	T
REVEL	Uncertain	0.48
Sift4G	Benign	0.15	T
Polyphen		0.13	B
Vest4		0.30
MutPred		0.61		Gain of disorder (P = 0.0358)
MVP		0.76
MPC		0.30
ClinPred		0.33	T
GERP RS		3.7
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.12
gMVP		0.49
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -5

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

Other links and lift over

dbSNP: rs762000221; hg19: chr8-48691160;