rs56047668

Variant names:

• chr8-47900422-C-A
• rs56047668
• NM_006904.7:c.3315G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-47900422-C-A
• chr8-47900422-C-T

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.3315G>T​(p.Val1105Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,611,894 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1105V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (5 hom.)
• Consequence: PRKDC NM_006904.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.191
• Publications: 1 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 8-47900422-C-A is Benign according to our data. Variant chr8-47900422-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.191 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.3315G>T	p.Val1105Val	synonymous	Exon 28 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.3315G>T	p.Val1105Val	synonymous	Exon 28 of 85	NP_001075109.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	ENST00000314191.7	TSL:1 MANE Select	c.3315G>T	p.Val1105Val	synonymous	Exon 28 of 86	ENSP00000313420.3
	PRKDC	ENST00000338368.7	TSL:1	c.3315G>T	p.Val1105Val	synonymous	Exon 28 of 85	ENSP00000345182.4
	PRKDC	ENST00000911724.1		c.3315G>T	p.Val1105Val	synonymous	Exon 28 of 86	ENSP00000581783.1

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 231 AN: 152192 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00172 AC: 423 AN: 245558 AF XY: 0.00183

Gnomad AFR exome AF: 0.000330

Gnomad AMR exome AF: 0.0000879

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00138 AC: 2013 AN: 1459584 Hom.: 5 Cov.: 30 AF XY: 0.00141 AC XY: 1021 AN XY: 725722

African (AFR) AF: 0.000299 AC: 10 AN: 33464

American (AMR) AF: 0.0000675 AC: 3 AN: 44460

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00115 AC: 98 AN: 85444

European-Finnish (FIN) AF: 0.00883 AC: 471 AN: 53312

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

European-Non Finnish (NFE) AF: 0.00122 AC: 1354 AN: 1111078

Other (OTH) AF: 0.00114 AC: 69 AN: 60308

GnomAD4 genome AF: 0.00152 AC: 231 AN: 152310 Hom.: 2 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74482

African (AFR) AF: 0.000192 AC: 8 AN: 41582

American (AMR) AF: 0.000327 AC: 5 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.0116 AC: 123 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 68024

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.000824

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	PRKDC-related disorder (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	-0.65
CADD	Benign	4.5
DANN	Benign	0.65
PhyloP100		-0.19
Mutation Taster		=99/1	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: rs56047668; hg19: chr8-48812982; COSMIC: COSV58057698;