8-47927810-G-C

Variant names:

• chr8-47927810-G-C
• rs191477681
• NM_006904.7:c.2220C>G

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.2220C>G​(p.Ile740Met) 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I740I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62
• 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=0.22707123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.2220C>G	p.Ile740Met	missense_variant	Exon 20 of 86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.2220C>G	p.Ile740Met	missense_variant	Exon 20 of 85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.2220C>G	p.Ile740Met	missense_variant	Exon 20 of 86	1	NM_006904.7	ENSP00000313420.3
PRKDC	ENST00000338368.7	c.2220C>G	p.Ile740Met	missense_variant	Exon 20 of 85	1		ENSP00000345182.4
PRKDC	ENST00000541488.1	n.159C>G		non_coding_transcript_exon_variant	Exon 2 of 3	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

not specified Uncertain:1

Feb 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I740M variant (also known as c.2220C>G), located in coding exon 20 of the PRKDC gene, results from a C to G substitution at nucleotide position 2220. The isoleucine at codon 740 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	0.086
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.86	D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.94	T
PhyloP100		1.6
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.11
Sift	Benign	0.20	T;T
Sift4G	Benign	0.090	T;T
Polyphen		0.62	P;P
Vest4		0.43
MutPred		0.30		Loss of catalytic residue at E742 (P = 0.3895);Loss of catalytic residue at E742 (P = 0.3895);
MVP		0.62
MPC		0.44
ClinPred		0.96	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.52
Mutation Taster		=84/16	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: rs191477681; hg19: chr8-48840370;