chr8-47778507-G-A

Variant names:

• chr8-47778507-G-A
• rs8178249
• NM_006904.7:c.11805C>T

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.11805C>T​(p.Gly3935Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 1,613,570 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (49 hom.)
• Consequence: PRKDC NM_006904.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.33
• Publications: 8 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.005).
• BP6: Variant 8-47778507-G-A is Benign according to our data. Variant chr8-47778507-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 379753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00534 (7805/1461262) while in subpopulation MID AF = 0.0323 (186/5766). AF 95% confidence interval is 0.0285. There are 49 homozygotes in GnomAdExome4. There are 3825 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	NM_006904.7	MANE Select	c.11805C>T	p.Gly3935Gly	synonymous	Exon 83 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.11712C>T	p.Gly3904Gly	synonymous	Exon 82 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.11805C>T	p.Gly3935Gly	synonymous	Exon 83 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.11712C>T	p.Gly3904Gly	synonymous	Exon 82 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.11814C>T	p.Gly3938Gly	synonymous	Exon 83 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes AF: 0.00561 AC: 854 AN: 152190 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00664

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00533 AC: 1323 AN: 248176 AF XY: 0.00524

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00384

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.00599

Gnomad OTH exome AF: 0.00580

GnomAD4 exome AF: 0.00534 AC: 7805 AN: 1461262 Hom.: 49 Cov.: 31 AF XY: 0.00526 AC XY: 3825 AN XY: 726852

African (AFR) AF: 0.00173 AC: 58 AN: 33466

American (AMR) AF: 0.00403 AC: 180 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00900 AC: 235 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.000987 AC: 85 AN: 86154

European-Finnish (FIN) AF: 0.0153 AC: 818 AN: 53346

Middle Eastern (MID) AF: 0.0323 AC: 186 AN: 5766

European-Non Finnish (NFE) AF: 0.00527 AC: 5861 AN: 1111716

Other (OTH) AF: 0.00631 AC: 381 AN: 60364

GnomAD4 genome AF: 0.00560 AC: 853 AN: 152308 Hom.: 8 Cov.: 32 AF XY: 0.00600 AC XY: 447 AN XY: 74468

African (AFR) AF: 0.00144 AC: 60 AN: 41570

American (AMR) AF: 0.00817 AC: 125 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.0151 AC: 160 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00663 AC: 451 AN: 68022

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00565 Hom.: 13

Bravo AF: 0.00483

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Severe combined immunodeficiency due to DNA-PKcs deficiency (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.23
DANN	Benign	0.46
PhyloP100		-4.3
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=98/2	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: rs8178249; hg19: chr8-48691068; COSMIC: COSV100040225; COSMIC: COSV100040225;