rs6992074

Variant names:

• chr8-47879638-A-C
• rs6992074
• NM_006904.7:c.5088T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006904.7(PRKDC):​c.5088T>G​(p.Leu1696Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,583,438 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (36 hom.)
• Consequence: PRKDC NM_006904.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.935
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 8-47879638-A-C is Benign according to our data. Variant chr8-47879638-A-C is described in ClinVar as Benign. ClinVar VariationId is 379439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.935 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0111 (1691/152218) while in subpopulation AFR AF = 0.0378 (1568/41516). AF 95% confidence interval is 0.0362. There are 43 homozygotes in GnomAd4. There are 790 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 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.5088T>G	p.Leu1696Leu	synonymous	Exon 39 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.5088T>G	p.Leu1696Leu	synonymous	Exon 39 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.5088T>G	p.Leu1696Leu	synonymous	Exon 39 of 86	ENSP00000313420.3
	PRKDC	ENST00000338368.7	TSL:1	c.5088T>G	p.Leu1696Leu	synonymous	Exon 39 of 85	ENSP00000345182.4

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1676 AN: 152100 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00294 AC: 615 AN: 208936 AF XY: 0.00205

Gnomad AFR exome AF: 0.0381

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00165

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000147

Gnomad OTH exome AF: 0.00211

GnomAD4 exome AF: 0.00123 AC: 1762 AN: 1431220 Hom.: 36 Cov.: 31 AF XY: 0.00105 AC XY: 746 AN XY: 709328

African (AFR) AF: 0.0390 AC: 1265 AN: 32472

American (AMR) AF: 0.00303 AC: 118 AN: 38886

Ashkenazi Jewish (ASJ) AF: 0.00177 AC: 45 AN: 25404

East Asian (EAS) AF: 0.00 AC: 0 AN: 38714

South Asian (SAS) AF: 0.000165 AC: 13 AN: 78856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52350

Middle Eastern (MID) AF: 0.00332 AC: 19 AN: 5726

European-Non Finnish (NFE) AF: 0.0000810 AC: 89 AN: 1099410

Other (OTH) AF: 0.00359 AC: 213 AN: 59402

GnomAD4 genome AF: 0.0111 AC: 1691 AN: 152218 Hom.: 43 Cov.: 32 AF XY: 0.0106 AC XY: 790 AN XY: 74436

African (AFR) AF: 0.0378 AC: 1568 AN: 41516

American (AMR) AF: 0.00471 AC: 72 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68018

Other (OTH) AF: 0.0118 AC: 25 AN: 2110

Alfa AF: 0.00397 Hom.: 40

Bravo AF: 0.0124

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.2
DANN	Benign	0.76
PhyloP100		0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=94/6	polymorphism

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: rs6992074; hg19: chr8-48792199;