rs201231274

Variant names:

• chr8-47954424-G-C
• rs201231274
• NM_006904.7:c.422C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-47954424-G-C
• chr8-47954424-G-A
• chr8-47954424-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_006904.7(PRKDC):​c.422C>G​(p.Ser141Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000376 in 1,349,220 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S141S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 5.57
• Publications: 2 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050324798).
• BP6: Variant 8-47954424-G-C is Benign according to our data. Variant chr8-47954424-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 542024.

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.422C>G	p.Ser141Cys	missense	Exon 5 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.422C>G	p.Ser141Cys	missense	Exon 5 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.422C>G	p.Ser141Cys	missense	Exon 5 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.422C>G	p.Ser141Cys	missense	Exon 5 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.422C>G	p.Ser141Cys	missense	Exon 5 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 329 AN: 151464 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00751

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000300 AC: 39 AN: 129850 AF XY: 0.000247

Gnomad AFR exome AF: 0.00448

Gnomad AMR exome AF: 0.000308

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: 0.000573

GnomAD4 exome AF: 0.000148 AC: 177 AN: 1197638 Hom.: 0 Cov.: 20 AF XY: 0.000122 AC XY: 72 AN XY: 590088

African (AFR) AF: 0.00484 AC: 128 AN: 26422

American (AMR) AF: 0.000370 AC: 10 AN: 27050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21844

East Asian (EAS) AF: 0.00 AC: 0 AN: 33400

South Asian (SAS) AF: 0.0000172 AC: 1 AN: 58034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46494

Middle Eastern (MID) AF: 0.000196 AC: 1 AN: 5094

European-Non Finnish (NFE) AF: 0.00000430 AC: 4 AN: 929462

Other (OTH) AF: 0.000662 AC: 33 AN: 49838

GnomAD4 genome AF: 0.00218 AC: 330 AN: 151582 Hom.: 0 Cov.: 33 AF XY: 0.00199 AC XY: 147 AN XY: 74030

African (AFR) AF: 0.00751 AC: 310 AN: 41286

American (AMR) AF: 0.00105 AC: 16 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67934

Other (OTH) AF: 0.00143 AC: 3 AN: 2102

Alfa AF: 0.0000638 Hom.: 0

Bravo AF: 0.00261

ESP6500AA AF: 0.00658 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000280 AC: 30

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Severe combined immunodeficiency due to DNA-PKcs deficiency (2)
-	-	1	not specified (1)
-	-	1	PRKDC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.075
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.73	T
PhyloP100		5.6
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.11
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.15	B
Vest4		0.36
MVP		0.66
MPC		0.19
ClinPred		0.029	T
GERP RS		4.3
Varity_R		0.25
gMVP		0.22
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201231274; hg19: chr8-48866984;