chr8-47798394-A-G

Variant names:

• chr8-47798394-A-G
• rs7830743
• NM_006904.7:c.10301T>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.10301T>C​(p.Ile3434Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0775 in 1,593,232 control chromosomes in the GnomAD database, including 8,905 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2189 hom., cov: 32)
  • Exomes 𝑓: 0.072 (6716 hom.)
• Consequence: PRKDC NM_006904.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.231
• Publications: 38 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 (MetaRNN=0.0017988086).
• BP6: Variant 8-47798394-A-G is Benign according to our data. Variant chr8-47798394-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 379415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 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.10301T>C	p.Ile3434Thr	missense	Exon 73 of 86	NP_008835.5
	PRKDC	NM_001081640.2		c.10301T>C	p.Ile3434Thr	missense	Exon 73 of 85	NP_001075109.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKDC	ENST00000314191.7	TSL:1 MANE Select	c.10301T>C	p.Ile3434Thr	missense	Exon 73 of 86	ENSP00000313420.3
	PRKDC	ENST00000338368.7	TSL:1	c.10301T>C	p.Ile3434Thr	missense	Exon 73 of 85	ENSP00000345182.4
	PRKDC	ENST00000697603.1		c.2978T>C	p.Ile993Thr	missense	Exon 20 of 33	ENSP00000513358.1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20257 AN: 152122 Hom.: 2188 Cov.: 32

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.0910

Gnomad EAS AF: 0.0838

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.0322

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0496

Gnomad OTH AF: 0.135

GnomAD2 exomes AF: 0.119 AC: 27068 AN: 226646 AF XY: 0.112

Gnomad AFR exome AF: 0.281

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.0935

Gnomad EAS exome AF: 0.0689

Gnomad FIN exome AF: 0.0388

Gnomad NFE exome AF: 0.0542

Gnomad OTH exome AF: 0.0990

GnomAD4 exome AF: 0.0716 AC: 103208 AN: 1440992 Hom.: 6716 Cov.: 31 AF XY: 0.0728 AC XY: 52116 AN XY: 715512

African (AFR) AF: 0.289 AC: 9376 AN: 32462

American (AMR) AF: 0.306 AC: 12287 AN: 40150

Ashkenazi Jewish (ASJ) AF: 0.0923 AC: 2309 AN: 25012

East Asian (EAS) AF: 0.0884 AC: 3498 AN: 39566

South Asian (SAS) AF: 0.156 AC: 12849 AN: 82412

European-Finnish (FIN) AF: 0.0387 AC: 2046 AN: 52850

Middle Eastern (MID) AF: 0.0961 AC: 543 AN: 5652

European-Non Finnish (NFE) AF: 0.0500 AC: 55174 AN: 1103376

Other (OTH) AF: 0.0861 AC: 5126 AN: 59512

GnomAD4 genome AF: 0.133 AC: 20284 AN: 152240 Hom.: 2189 Cov.: 32 AF XY: 0.133 AC XY: 9914 AN XY: 74450

African (AFR) AF: 0.272 AC: 11279 AN: 41516

American (AMR) AF: 0.213 AC: 3254 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0910 AC: 316 AN: 3472

East Asian (EAS) AF: 0.0840 AC: 435 AN: 5180

South Asian (SAS) AF: 0.164 AC: 790 AN: 4828

European-Finnish (FIN) AF: 0.0322 AC: 342 AN: 10610

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0496 AC: 3376 AN: 68030

Other (OTH) AF: 0.137 AC: 289 AN: 2112

Alfa AF: 0.0854 Hom.: 1979

Bravo AF: 0.158

TwinsUK AF: 0.0520 AC: 193

ALSPAC AF: 0.0496 AC: 191

ESP6500AA AF: 0.261 AC: 975

ESP6500EA AF: 0.0568 AC: 467

ExAC AF: 0.115 AC: 13833

Asia WGS AF: 0.144 AC: 501 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)
-	-	1	Severe combined immunodeficiency due to DNA-PKcs deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.042
DANN	Benign	0.23
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.40	N
PhyloP100		-0.23
PrimateAI	Benign	0.27	T
REVEL	Benign	0.075
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.0070
MPC		0.21
ClinPred		0.0021	T
GERP RS		-7.7
Varity_R		0.039
gMVP		0.048
Mutation Taster		=96/4	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: rs7830743; hg19: chr8-48710955; COSMIC: COSV58047120;