chr8-47817446-T-G

Variant names:

• chr8-47817446-T-G
• rs140578467
• NM_006904.7:c.9557+4A>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_006904.7(PRKDC):​c.9557+4A>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00027 in 1,575,080 control chromosomes in the GnomAD database, including 2 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: PRKDC NM_006904.7 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.68
• 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 8-47817446-T-G is Benign according to our data. Variant chr8-47817446-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 542003.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.9557+4A>C		splice_region_variant, intron_variant	Intron 68 of 85	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.9557+4A>C		splice_region_variant, intron_variant	Intron 68 of 84		NP_001075109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKDC	ENST00000314191.7	c.9557+4A>C		splice_region_variant, intron_variant	Intron 68 of 85	1	NM_006904.7	ENSP00000313420.3
PRKDC	ENST00000338368.7	c.9557+4A>C		splice_region_variant, intron_variant	Intron 68 of 84	1		ENSP00000345182.4
PRKDC	ENST00000697603.1	c.2234+4A>C		splice_region_variant, intron_variant	Intron 15 of 32			ENSP00000513358.1
PRKDC	ENST00000697607.1	n.1089+4A>C		splice_region_variant, intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152216 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00495

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000419 AC: 94 AN: 224364 AF XY: 0.000265

Gnomad AFR exome AF: 0.00546

Gnomad AMR exome AF: 0.000323

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000300

Gnomad OTH exome AF: 0.000354

GnomAD4 exome AF: 0.000142 AC: 202 AN: 1422746 Hom.: 0 Cov.: 27 AF XY: 0.000116 AC XY: 82 AN XY: 706372

African (AFR) AF: 0.00487 AC: 160 AN: 32874

American (AMR) AF: 0.000506 AC: 21 AN: 41520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25606

East Asian (EAS) AF: 0.00 AC: 0 AN: 39250

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52494

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083510

Other (OTH) AF: 0.000322 AC: 19 AN: 59072

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152334 Hom.: 2 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74490

African (AFR) AF: 0.00493 AC: 205 AN: 41568

American (AMR) AF: 0.000784 AC: 12 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68044

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000830 Hom.: 1

Bravo AF: 0.00173

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe combined immunodeficiency due to DNA-PKcs deficiency Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.88
PhyloP100		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140578467; hg19: chr8-48730007;