rs8177999

Variant names:

• chr8-47960111-C-A
• rs8177999
• NM_006904.7:c.16G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-47960111-C-A
• chr8-47960111-C-T
• chr8-47960111-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006904.7(PRKDC):​c.16G>T​(p.Ala6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0058 in 1,504,624 control chromosomes in the GnomAD database, including 352 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.029 (216 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (136 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.301
• Publications: 15 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014592409).
• BP6: Variant 8-47960111-C-A is Benign according to our data. Variant chr8-47960111-C-A is described in ClinVar as Benign. ClinVar VariationId is 379772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0947 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006904.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	NM_006904.7	MANE Select	c.16G>T	p.Ala6Ser	missense	Exon 1 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.16G>T	p.Ala6Ser	missense	Exon 1 of 85	NP_001075109.1	P78527-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	ENST00000314191.7	TSL:1 MANE Select	c.16G>T	p.Ala6Ser	missense	Exon 1 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.16G>T	p.Ala6Ser	missense	Exon 1 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.16G>T	p.Ala6Ser	missense	Exon 1 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 4328 AN: 152168 Hom.: 216 Cov.: 32

Gnomad AFR AF: 0.0972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0272

GnomAD2 exomes AF: 0.00550 AC: 585 AN: 106398 AF XY: 0.00463

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.00399

Gnomad ASJ exome AF: 0.0208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000738

Gnomad OTH exome AF: 0.00576

GnomAD4 exome AF: 0.00324 AC: 4379 AN: 1352344 Hom.: 136 Cov.: 31 AF XY: 0.00299 AC XY: 1991 AN XY: 664850

African (AFR) AF: 0.0961 AC: 2713 AN: 28232

American (AMR) AF: 0.00574 AC: 194 AN: 33782

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 566 AN: 24240

East Asian (EAS) AF: 0.00 AC: 0 AN: 32774

South Asian (SAS) AF: 0.000261 AC: 20 AN: 76732

European-Finnish (FIN) AF: 0.0000301 AC: 1 AN: 33254

Middle Eastern (MID) AF: 0.00526 AC: 21 AN: 3996

European-Non Finnish (NFE) AF: 0.000401 AC: 426 AN: 1063036

Other (OTH) AF: 0.00778 AC: 438 AN: 56298

GnomAD4 genome AF: 0.0285 AC: 4341 AN: 152280 Hom.: 216 Cov.: 32 AF XY: 0.0274 AC XY: 2041 AN XY: 74456

African (AFR) AF: 0.0972 AC: 4041 AN: 41562

American (AMR) AF: 0.00856 AC: 131 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68016

Other (OTH) AF: 0.0270 AC: 57 AN: 2114

Alfa AF: 0.00622 Hom.: 23

Bravo AF: 0.0318

ESP6500AA AF: 0.0575 AC: 146

ESP6500EA AF: 0.00155 AC: 9

ExAC AF: 0.00437 AC: 268

Asia WGS AF: 0.00694 AC: 24 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Severe combined immunodeficiency due to DNA-PKcs deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.82
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.30
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.020
Sift	Benign	0.54	T
Sift4G	Benign	0.68	T
Polyphen		0.0030	B
Vest4		0.042
MVP		0.13
MPC		0.15
ClinPred		0.0054	T
GERP RS		-8.3
PromoterAI		0.29	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.024
gMVP		0.16
Mutation Taster		=100/0	polymorphism (auto)

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: rs8177999; hg19: chr8-48872671;