8-47933959-T-C

Variant names:

• chr8-47933959-T-C
• rs1231202
• NM_006904.7:c.1623+6A>G

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.1623+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.954 in 1,607,496 control chromosomes in the GnomAD database, including 732,409 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70905 hom., cov: 33)
  • Exomes 𝑓: 0.95 (661504 hom.)
• Consequence: PRKDC NM_006904.7 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.607
• Publications: 15 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=-0.87).
• BP6: Variant 8-47933959-T-C is Benign according to our data. Variant chr8-47933959-T-C is described in ClinVar as Benign. ClinVar VariationId is 379395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.983 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.1623+6A>G		splice_region_variant, intron_variant	Intron 15 of 85	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.1623+6A>G		splice_region_variant, intron_variant	Intron 15 of 84		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.1623+6A>G		splice_region_variant, intron_variant	Intron 15 of 85	1	NM_006904.7	ENSP00000313420.3
PRKDC	ENST00000338368.7	c.1623+6A>G		splice_region_variant, intron_variant	Intron 15 of 84	1		ENSP00000345182.4
PRKDC	ENST00000697591.1	n.1670A>G		non_coding_transcript_exon_variant	Exon 15 of 15

Frequencies

GnomAD3 genomes AF: 0.965 AC: 146844 AN: 152234 Hom.: 70839 Cov.: 33

Gnomad AFR AF: 0.991

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.962

Gnomad ASJ AF: 0.914

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.991

Gnomad FIN AF: 0.954

Gnomad MID AF: 0.956

Gnomad NFE AF: 0.949

Gnomad OTH AF: 0.959

GnomAD2 exomes AF: 0.961 AC: 238227 AN: 247968 AF XY: 0.961

Gnomad AFR exome AF: 0.992

Gnomad AMR exome AF: 0.975

Gnomad ASJ exome AF: 0.910

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.953

Gnomad NFE exome AF: 0.944

Gnomad OTH exome AF: 0.954

GnomAD4 exome AF: 0.953 AC: 1387255 AN: 1455144 Hom.: 661504 Cov.: 41 AF XY: 0.955 AC XY: 690910 AN XY: 723764

African (AFR) AF: 0.992 AC: 33092 AN: 33374

American (AMR) AF: 0.974 AC: 43335 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 23603 AN: 26002

East Asian (EAS) AF: 1.00 AC: 39601 AN: 39608

South Asian (SAS) AF: 0.993 AC: 84821 AN: 85392

European-Finnish (FIN) AF: 0.951 AC: 50610 AN: 53196

Middle Eastern (MID) AF: 0.958 AC: 4419 AN: 4614

European-Non Finnish (NFE) AF: 0.948 AC: 1050351 AN: 1108460

Other (OTH) AF: 0.957 AC: 57423 AN: 59996

GnomAD4 genome AF: 0.965 AC: 146969 AN: 152352 Hom.: 70905 Cov.: 33 AF XY: 0.966 AC XY: 71948 AN XY: 74494

African (AFR) AF: 0.991 AC: 41204 AN: 41582

American (AMR) AF: 0.962 AC: 14730 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.914 AC: 3175 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5186 AN: 5188

South Asian (SAS) AF: 0.992 AC: 4789 AN: 4830

European-Finnish (FIN) AF: 0.954 AC: 10129 AN: 10618

Middle Eastern (MID) AF: 0.959 AC: 282 AN: 294

European-Non Finnish (NFE) AF: 0.949 AC: 64539 AN: 68038

Other (OTH) AF: 0.959 AC: 2026 AN: 2112

Alfa AF: 0.953 Hom.: 79447

Bravo AF: 0.965

Asia WGS AF: 0.996 AC: 3464 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Oct 20, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 100% of patients studied by a panel of primary immunodeficiencies. Number of patients: 95. Only high quality variants are reported. -

Severe combined immunodeficiency due to DNA-PKcs deficiency Benign:2

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.15
DANN	Benign	0.51
PhyloP100		-0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1231202; hg19: chr8-48846519;