rs79703138

Variant names:

• chr8-47858853-TCTC-T
• rs79703138
• NM_006904.7:c.6338_6340delGAG

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PM4_Supporting BP6_Very_Strong BS2

The NM_006904.7(PRKDC):​c.6338_6340delGAG​(p.Gly2113del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,613,134 control chromosomes in the GnomAD database, including 116 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G2113G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0058 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (89 hom.)
• Consequence: PRKDC NM_006904.7 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.96
• Publications: 6 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 -11 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006904.7. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 8-47858853-TCTC-T is Benign according to our data. Variant chr8-47858853-TCTC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 542029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 27 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.6338_6340delGAG	p.Gly2113del	disruptive_inframe_deletion	Exon 47 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.6338_6340delGAG	p.Gly2113del	disruptive_inframe_deletion	Exon 47 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.6338_6340delGAG	p.Gly2113del	disruptive_inframe_deletion	Exon 47 of 86	ENSP00000313420.3
	PRKDC	ENST00000338368.7	TSL:1	c.6338_6340delGAG	p.Gly2113del	disruptive_inframe_deletion	Exon 47 of 85	ENSP00000345182.4
	PRKDC	ENST00000697609.1		n.499_501delGAG		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00578 AC: 880 AN: 152136 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0675

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00712 AC: 1770 AN: 248556 AF XY: 0.00716

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0110

Gnomad FIN exome AF: 0.0588

Gnomad NFE exome AF: 0.00217

Gnomad OTH exome AF: 0.00763

GnomAD4 exome AF: 0.00289 AC: 4219 AN: 1460880 Hom.: 89 AF XY: 0.00287 AC XY: 2082 AN XY: 726592

African (AFR) AF: 0.0000299 AC: 1 AN: 33462

American (AMR) AF: 0.0000895 AC: 4 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0115 AC: 458 AN: 39676

South Asian (SAS) AF: 0.000487 AC: 42 AN: 86222

European-Finnish (FIN) AF: 0.0540 AC: 2881 AN: 53330

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000588 AC: 653 AN: 1111292

Other (OTH) AF: 0.00295 AC: 178 AN: 60330

GnomAD4 genome AF: 0.00578 AC: 880 AN: 152254 Hom.: 27 Cov.: 32 AF XY: 0.00887 AC XY: 660 AN XY: 74424

African (AFR) AF: 0.0000722 AC: 3 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.0116 AC: 60 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0675 AC: 715 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00294 Hom.: 0

Bravo AF: 0.000876

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=73/27	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: rs79703138; hg19: chr8-48771414; COSMIC: COSV100042327;