chr8-47817446-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006904.7(PRKDC):​c.9557+4A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000351 in 1,422,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: PRKDC NM_006904.7 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKDC	NM_006904.7	c.9557+4A>G		splice_region_variant, intron_variant	Intron 68 of 85	ENST00000314191.7	NP_008835.5
PRKDC	NM_001081640.2	c.9557+4A>G		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>G		splice_region_variant, intron_variant	Intron 68 of 85	1	NM_006904.7	ENSP00000313420.3
PRKDC	ENST00000338368.7	c.9557+4A>G		splice_region_variant, intron_variant	Intron 68 of 84	1		ENSP00000345182.4
PRKDC	ENST00000697603.1	c.2234+4A>G		splice_region_variant, intron_variant	Intron 15 of 32			ENSP00000513358.1
PRKDC	ENST00000697607.1	n.1089+4A>G		splice_region_variant, intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000351 AC: 5 AN: 1422746 Hom.: 0 Cov.: 27 AF XY: 0.00000283 AC XY: 2 AN XY: 706372

African (AFR) AF: 0.00 AC: 0 AN: 32874

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 82716

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000461 AC: 5 AN: 1083510

Other (OTH) AF: 0.00 AC: 0 AN: 59072

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.86
PhyloP100		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;