chr8-47778773-G-T

Variant names:

• chr8-47778773-G-T
• rs550306617
• NM_006904.7:c.11606C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006904.7(PRKDC):​c.11606C>A​(p.Thr3869Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3869M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.243
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.084242016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.11606C>A	p.Thr3869Lys	missense_variant	Exon 82 of 86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.11513C>A	p.Thr3838Lys	missense_variant	Exon 81 of 85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.11606C>A	p.Thr3869Lys	missense_variant	Exon 82 of 86	1	NM_006904.7	ENSP00000313420.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.1
DANN	Benign	0.45
DEOGEN2	Benign	0.067	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.084	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.10	N;.
PhyloP100		0.24
PrimateAI	Benign	0.27	T
REVEL	Benign	0.053
Sift4G	Benign	0.49	T;T
Polyphen		0.029	B;.
Vest4		0.28
MutPred		0.48		Gain of methylation at T3869 (P = 0.0144);.;
MVP		0.47
MPC		0.20
ClinPred		0.035	T
GERP RS		2.2
PromoterAI		-0.033	Neutral
Varity_R		0.044
gMVP		0.25
Mutation Taster		=92/8	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: rs550306617; hg19: chr8-48691334;