NM_006904.7:c.10721C>T

Variant names:

• chr8-47789188-G-A
• rs587777686
• NM_006904.7:c.10721C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_006904.7(PRKDC):​c.10721C>T​(p.Ala3574Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A3574A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.20

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-47789188-G-A is Pathogenic according to our data. Variant chr8-47789188-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 154323.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.10721C>T	p.Ala3574Val	missense_variant	Exon 75 of 86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.10721C>T	p.Ala3574Val	missense_variant	Exon 75 of 85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.10721C>T	p.Ala3574Val	missense_variant	Exon 75 of 86	1	NM_006904.7	ENSP00000313420.3
PRKDC	ENST00000338368.7	c.10721C>T	p.Ala3574Val	missense_variant	Exon 75 of 85	1		ENSP00000345182.4
PRKDC	ENST00000697603.1	c.3398C>T	p.Ala1133Val	missense_variant	Exon 22 of 33			ENSP00000513358.1
PRKDC	ENST00000697602.1	n.1294C>T		non_coding_transcript_exon_variant	Exon 7 of 18

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Jul 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.0034	T
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Uncertain	0.55	T
REVEL	Benign	0.15
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.95	P;.
Vest4		0.77
MutPred		0.36		Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);
MVP		0.69
MPC		0.65
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777686; hg19: chr8-48701749;