chr8-47931496-G-GT

Variant names:

• chr8-47931496-G-GT
• rs546905091
• NM_006904.7:c.1777-710dupA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_006904.7(PRKDC):​c.1777-710dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 143,908 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0023 (1 hom., cov: 32)
• Consequence: PRKDC NM_006904.7 intron
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 B:1
• Conservation: PhyloP100: -0.559
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.1777-710dupA		intron	N/A	NP_008835.5
	PRKDC	NM_001081640.2		c.1777-710dupA		intron	N/A	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.1777-710_1777-709insA		intron	N/A	ENSP00000313420.3	P78527-1
	PRKDC	ENST00000338368.7	TSL:1	c.1777-710_1777-709insA		intron	N/A	ENSP00000345182.4	P78527-2
	PRKDC	ENST00000911724.1		c.1777-710_1777-709insA		intron	N/A	ENSP00000581783.1

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 331 AN: 143872 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000911

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00231

Gnomad ASJ AF: 0.00239

Gnomad EAS AF: 0.000405

Gnomad SAS AF: 0.00736

Gnomad FIN AF: 0.00811

Gnomad MID AF: 0.0100

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.00204

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00235 AC: 338 AN: 143908 Hom.: 1 Cov.: 32 AF XY: 0.00263 AC XY: 184 AN XY: 69970

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00101 AC: 40 AN: 39578

American (AMR) AF: 0.00231 AC: 33 AN: 14306

Ashkenazi Jewish (ASJ) AF: 0.00239 AC: 8 AN: 3352

East Asian (EAS) AF: 0.000609 AC: 3 AN: 4930

South Asian (SAS) AF: 0.00762 AC: 34 AN: 4462

European-Finnish (FIN) AF: 0.00811 AC: 73 AN: 8998

Middle Eastern (MID) AF: 0.0109 AC: 3 AN: 276

European-Non Finnish (NFE) AF: 0.00213 AC: 139 AN: 65136

Other (OTH) AF: 0.00254 AC: 5 AN: 1970

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000272 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	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
PhyloP100		-0.56
Mutation Taster		=37/63	disease causing (ClinVar)

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: rs546905091; hg19: chr8-48844056; COSMIC: COSV58052215; COSMIC: COSV58052215;