rs45438803

Variant names:

• chr8-47929994-T-C
• rs45438803
• NM_006904.7:c.1911A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006904.7(PRKDC):​c.1911A>G​(p.Lys637Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00598 in 1,604,406 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (38 hom.)
• Consequence: PRKDC NM_006904.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.125
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 8-47929994-T-C is Benign according to our data. Variant chr8-47929994-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.125 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 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.1911A>G	p.Lys637Lys	synonymous	Exon 18 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.1911A>G	p.Lys637Lys	synonymous	Exon 18 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.1911A>G	p.Lys637Lys	synonymous	Exon 18 of 86	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.1911A>G	p.Lys637Lys	synonymous	Exon 18 of 85	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.1911A>G	p.Lys637Lys	synonymous	Exon 18 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes AF: 0.00405 AC: 616 AN: 152206 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00697

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00401 AC: 961 AN: 239736 AF XY: 0.00411

Gnomad AFR exome AF: 0.000655

Gnomad AMR exome AF: 0.00239

Gnomad ASJ exome AF: 0.00132

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00177

Gnomad NFE exome AF: 0.00700

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00618 AC: 8981 AN: 1452082 Hom.: 38 Cov.: 30 AF XY: 0.00595 AC XY: 4294 AN XY: 721852

African (AFR) AF: 0.000939 AC: 31 AN: 33024

American (AMR) AF: 0.00242 AC: 102 AN: 42202

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 32 AN: 25944

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39524

South Asian (SAS) AF: 0.000866 AC: 72 AN: 83126

European-Finnish (FIN) AF: 0.00214 AC: 114 AN: 53352

Middle Eastern (MID) AF: 0.000697 AC: 4 AN: 5738

European-Non Finnish (NFE) AF: 0.00749 AC: 8302 AN: 1109096

Other (OTH) AF: 0.00538 AC: 323 AN: 60076

GnomAD4 genome AF: 0.00404 AC: 616 AN: 152324 Hom.: 2 Cov.: 32 AF XY: 0.00379 AC XY: 282 AN XY: 74496

African (AFR) AF: 0.00154 AC: 64 AN: 41580

American (AMR) AF: 0.00340 AC: 52 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00697 AC: 474 AN: 68020

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00544 Hom.: 2

Bravo AF: 0.00428

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00629

EpiControl AF: 0.00607

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	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
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.6
DANN	Benign	0.61
PhyloP100		-0.13
Mutation Taster		=100/0	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: rs45438803; hg19: chr8-48842554; COSMIC: COSV104628506;