rs754453280

Variant names:

• chr8-47960110-G-A
• rs754453280
• NM_006904.7:c.17C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-47960110-G-A
• chr8-47960110-G-C
• chr8-47960110-G-T

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.17C>T​(p.Ala6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000886 in 1,354,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.332
• 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]

MCM4 (HGNC:6947): (minichromosome maintenance complex component 4) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. The MCM complex consisting of this protein and MCM2, 6 and 7 proteins possesses DNA helicase activity, and may act as a DNA unwinding enzyme. The phosphorylation of this protein by CDC2 kinase reduces the DNA helicase activity and chromatin binding of the MCM complex. This gene is mapped to a region on the chromosome 8 head-to-head next to the PRKDC/DNA-PK, a DNA-activated protein kinase involved in the repair of DNA double-strand breaks. Alternatively spliced transcript variants encoding the same protein have been reported. [provided by RefSeq, Jul 2008]

MCM4 Gene-Disease associations (from GenCC):

• primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

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=0.061723173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.17C>T	p.Ala6Val	missense_variant	Exon 1 of 86	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.17C>T	p.Ala6Val	missense_variant	Exon 1 of 85		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.17C>T	p.Ala6Val	missense_variant	Exon 1 of 86	1	NM_006904.7	ENSP00000313420.3
PRKDC	ENST00000338368.7	c.17C>T	p.Ala6Val	missense_variant	Exon 1 of 85	1		ENSP00000345182.4
PRKDC	ENST00000697591.1	n.58C>T		non_coding_transcript_exon_variant	Exon 1 of 15
MCM4	ENST00000518221.5	c.-225G>A		upstream_gene_variant		4		ENSP00000430329.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000183 AC: 2 AN: 109358 AF XY: 0.0000330

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000886 AC: 12 AN: 1354662 Hom.: 0 Cov.: 31 AF XY: 0.00000901 AC XY: 6 AN XY: 665954

African (AFR) AF: 0.0000350 AC: 1 AN: 28554

American (AMR) AF: 0.0000882 AC: 3 AN: 34018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24348

East Asian (EAS) AF: 0.00 AC: 0 AN: 33094

South Asian (SAS) AF: 0.0000389 AC: 3 AN: 77050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4004

European-Non Finnish (NFE) AF: 0.00000376 AC: 4 AN: 1063922

Other (OTH) AF: 0.0000177 AC: 1 AN: 56394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000158 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Aug 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A6V variant (also known as c.17C>T), located in coding exon 1 of the PRKDC gene, results from a C to T substitution at nucleotide position 17. The alanine at codon 6 is replaced by valine, an amino acid with 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. -

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

Jul 05, 2022

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. ClinVar contains an entry for this variant (Variation ID: 571987). This variant has not been reported in the literature in individuals affected with PRKDC-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 6 of the PRKDC protein (p.Ala6Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.33
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.036
Sift	Benign	0.030	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		0.22	B;B
Vest4		0.084
MutPred		0.15		Loss of disorder (P = 0.0435);Loss of disorder (P = 0.0435);
MVP		0.24
MPC		0.24
ClinPred		0.37	T
GERP RS		-1.0
PromoterAI		0.090	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.040
gMVP		0.24
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754453280; hg19: chr8-48872670;