8-47774281-T-G

Variant names:

• chr8-47774281-T-G
• NM_006904.7:c.12279A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006904.7(PRKDC):​c.12279A>C​(p.Glu4093Asp) 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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.338
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03140807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.12279A>C	p.Glu4093Asp	missense_variant	Exon 86 of 86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.12186A>C	p.Glu4062Asp	missense_variant	Exon 85 of 85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.12279A>C	p.Glu4093Asp	missense_variant	Exon 86 of 86	1	NM_006904.7	ENSP00000313420.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 10, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with PRKDC-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 4093 of the PRKDC protein (p.Glu4093Asp). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.55
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.031	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.6	M;.
PhyloP100		-0.34
PrimateAI	Benign	0.31	T
REVEL	Benign	0.060
Sift4G	Benign	0.46	T;T
Polyphen		0.0	B;.
Vest4		0.035
MutPred		0.099		Loss of loop (P = 0.1258);.;
MVP		0.55
MPC		0.16
ClinPred		0.32	T
GERP RS		-7.6
Varity_R		0.12
gMVP		0.35
Mutation Taster		=93/7	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

hg19: chr8-48686842;