8-47774178-T-G

Variant names:

• chr8-47774178-T-G
• NM_006904.7:c.12382A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006904.7(PRKDC):​c.12382A>C​(p.Met4128Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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: 3.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27322525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.12382A>C	p.Met4128Leu	missense_variant	Exon 86 of 86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.12289A>C	p.Met4097Leu	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.12382A>C	p.Met4128Leu	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

Aug 17, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRKDC protein function. ClinVar contains an entry for this variant (Variation ID: 2051824). This variant has not been reported in the literature in individuals affected with PRKDC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4128 of the PRKDC protein (p.Met4128Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.067	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.56	N;.
PrimateAI	Uncertain	0.50	T
REVEL	Uncertain	0.33
Sift4G	Benign	0.081	T;T
Polyphen		0.14	B;.
Vest4		0.45
MutPred		0.59		Loss of MoRF binding (P = 0.1119);.;
MVP		0.88
MPC		0.24
ClinPred		0.75	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.70

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-48686739;