20-44995017-C-G

Variant names:

• chr20-44995017-C-G
• rs6017460
• NM_006282.5:c.526-73C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006282.5(STK4):​c.526-73C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000327 in 917,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: STK4 NM_006282.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.17
• Publications: 0 publications found

Genes affected

STK4 (HGNC:11408): (serine/threonine kinase 4) The protein encoded by this gene is a cytoplasmic kinase that is structurally similar to the yeast Ste20p kinase, which acts upstream of the stress-induced mitogen-activated protein kinase cascade. The encoded protein can phosphorylate myelin basic protein and undergoes autophosphorylation. A caspase-cleaved fragment of the encoded protein has been shown to be capable of phosphorylating histone H2B. The particular phosphorylation catalyzed by this protein has been correlated with apoptosis, and it's possible that this protein induces the chromatin condensation observed in this process. [provided by RefSeq, Jul 2008]

STK4 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to STK4 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006282.5. 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
	STK4	NM_006282.5	MANE Select	c.526-73C>G		intron	N/A	NP_006273.1
	STK4	NM_001352385.2		c.526-73C>G		intron	N/A	NP_001339314.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK4	ENST00000372806.8	TSL:1 MANE Select	c.526-73C>G		intron	N/A	ENSP00000361892.3
	STK4	ENST00000499879.8	TSL:1	c.361-73C>G		intron	N/A	ENSP00000443514.1
	STK4	ENST00000372801.5	TSL:2	c.526-73C>G		intron	N/A	ENSP00000361887.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000327 AC: 3 AN: 917822 Hom.: 0 AF XY: 0.00000223 AC XY: 1 AN XY: 447776

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 19124

American (AMR) AF: 0.00 AC: 0 AN: 16010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13432

East Asian (EAS) AF: 0.00 AC: 0 AN: 24516

South Asian (SAS) AF: 0.0000394 AC: 1 AN: 25370

European-Finnish (FIN) AF: 0.0000283 AC: 1 AN: 35320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3692

European-Non Finnish (NFE) AF: 0.00000135 AC: 1 AN: 743326

Other (OTH) AF: 0.00 AC: 0 AN: 37032

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.41
DANN	Benign	0.49
PhyloP100		-2.2

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: rs6017460; hg19: chr20-43623658;