chr8-47929148-G-A

Variant names:

• chr8-47929148-G-A
• rs8178046
• NM_006904.7:c.2083C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006904.7(PRKDC):​c.2083C>T​(p.Pro695Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,579,236 control chromosomes in the GnomAD database, including 249 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (18 hom., cov: 32)
  • Exomes 𝑓: 0.015 (231 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.962
• Publications: 17 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030925572).
• BP6: Variant 8-47929148-G-A is Benign according to our data. Variant chr8-47929148-G-A is described in ClinVar as Benign. ClinVar VariationId is 379426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0112 (1713/152292) while in subpopulation NFE AF = 0.0194 (1323/68024). AF 95% confidence interval is 0.0186. There are 18 homozygotes in GnomAd4. There are 767 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	NM_006904.7	MANE Select	c.2083C>T	p.Pro695Ser	missense	Exon 19 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.2083C>T	p.Pro695Ser	missense	Exon 19 of 85	NP_001075109.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	ENST00000314191.7	TSL:1 MANE Select	c.2083C>T	p.Pro695Ser	missense	Exon 19 of 86	ENSP00000313420.3
	PRKDC	ENST00000338368.7	TSL:1	c.2083C>T	p.Pro695Ser	missense	Exon 19 of 85	ENSP00000345182.4
	PRKDC	ENST00000541488.1	TSL:3	n.22C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1717 AN: 152174 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00462

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00980 AC: 1956 AN: 199624 AF XY: 0.00918

Gnomad AFR exome AF: 0.00352

Gnomad AMR exome AF: 0.00455

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.0000668

Gnomad FIN exome AF: 0.00584

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0100

GnomAD4 exome AF: 0.0151 AC: 21536 AN: 1426944 Hom.: 231 Cov.: 30 AF XY: 0.0147 AC XY: 10352 AN XY: 706320

African (AFR) AF: 0.00241 AC: 79 AN: 32808

American (AMR) AF: 0.00515 AC: 206 AN: 39980

Ashkenazi Jewish (ASJ) AF: 0.00903 AC: 230 AN: 25472

East Asian (EAS) AF: 0.0000519 AC: 2 AN: 38556

South Asian (SAS) AF: 0.000504 AC: 41 AN: 81322

European-Finnish (FIN) AF: 0.00587 AC: 301 AN: 51282

Middle Eastern (MID) AF: 0.00942 AC: 54 AN: 5732

European-Non Finnish (NFE) AF: 0.0183 AC: 20033 AN: 1092630

Other (OTH) AF: 0.00997 AC: 590 AN: 59162

GnomAD4 genome AF: 0.0112 AC: 1713 AN: 152292 Hom.: 18 Cov.: 32 AF XY: 0.0103 AC XY: 767 AN XY: 74474

African (AFR) AF: 0.00277 AC: 115 AN: 41556

American (AMR) AF: 0.00752 AC: 115 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00462 AC: 49 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0194 AC: 1323 AN: 68024

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.0160 Hom.: 89

Bravo AF: 0.0117

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.00329 AC: 12

ESP6500EA AF: 0.0170 AC: 139

ExAC AF: 0.00776 AC: 928

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Sep 13, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.64
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.96
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.031
Sift	Benign	0.33	T
Sift4G	Benign	0.30	T
Polyphen		0.0090	B
Vest4		0.079
MVP		0.58
MPC		0.17
ClinPred		0.0042	T
GERP RS		2.2
Varity_R		0.037
gMVP		0.25
Mutation Taster		=99/1	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: rs8178046; hg19: chr8-48841708;