8-47888479-A-G

Variant names:

• chr8-47888479-A-G
• rs8178097
• NM_006904.7:c.4413+39T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006904.7(PRKDC):​c.4413+39T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0445 in 1,463,154 control chromosomes in the GnomAD database, including 1,658 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (123 hom., cov: 33)
  • Exomes 𝑓: 0.046 (1535 hom.)
• Consequence: PRKDC NM_006904.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.151
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-47888479-A-G is Benign according to our data. Variant chr8-47888479-A-G is described in ClinVar as Benign. ClinVar VariationId is 1266899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0574 is higher than 0.05.

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.4413+39T>C		intron	N/A	NP_008835.5
	PRKDC	NM_001081640.2		c.4413+39T>C		intron	N/A	NP_001075109.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	ENST00000314191.7	TSL:1 MANE Select	c.4413+39T>C		intron	N/A	ENSP00000313420.3
	PRKDC	ENST00000338368.7	TSL:1	c.4413+39T>C		intron	N/A	ENSP00000345182.4

Frequencies

GnomAD3 genomes AF: 0.0346 AC: 5266 AN: 152220 Hom.: 123 Cov.: 33

Gnomad AFR AF: 0.00914

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.0405

Gnomad ASJ AF: 0.0824

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0408

Gnomad FIN AF: 0.0234

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0477

Gnomad OTH AF: 0.0449

GnomAD2 exomes AF: 0.0412 AC: 5198 AN: 126280 AF XY: 0.0426

Gnomad AFR exome AF: 0.00775

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.0818

Gnomad EAS exome AF: 0.000457

Gnomad FIN exome AF: 0.0288

Gnomad NFE exome AF: 0.0532

Gnomad OTH exome AF: 0.0509

GnomAD4 exome AF: 0.0457 AC: 59915 AN: 1310816 Hom.: 1535 Cov.: 27 AF XY: 0.0461 AC XY: 29456 AN XY: 639060

African (AFR) AF: 0.00856 AC: 246 AN: 28736

American (AMR) AF: 0.0335 AC: 843 AN: 25170

Ashkenazi Jewish (ASJ) AF: 0.0834 AC: 1890 AN: 22654

East Asian (EAS) AF: 0.000263 AC: 9 AN: 34272

South Asian (SAS) AF: 0.0413 AC: 2672 AN: 64668

European-Finnish (FIN) AF: 0.0305 AC: 1439 AN: 47224

Middle Eastern (MID) AF: 0.0630 AC: 333 AN: 5284

European-Non Finnish (NFE) AF: 0.0486 AC: 49985 AN: 1028774

Other (OTH) AF: 0.0462 AC: 2498 AN: 54034

GnomAD4 genome AF: 0.0345 AC: 5261 AN: 152338 Hom.: 123 Cov.: 33 AF XY: 0.0339 AC XY: 2522 AN XY: 74494

African (AFR) AF: 0.00911 AC: 379 AN: 41586

American (AMR) AF: 0.0404 AC: 617 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0824 AC: 286 AN: 3470

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

South Asian (SAS) AF: 0.0402 AC: 194 AN: 4826

European-Finnish (FIN) AF: 0.0234 AC: 248 AN: 10618

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0477 AC: 3248 AN: 68040

Other (OTH) AF: 0.0445 AC: 94 AN: 2114

Alfa AF: 0.0435 Hom.: 68

Bravo AF: 0.0357

Asia WGS AF: 0.0160 AC: 57 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.1
DANN	Benign	0.55
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

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: rs8178097; hg19: chr8-48801040;