9-5126321-G-GC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_004972.4(JAK2):c.3178-12_3178-11insC variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,545,100 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (6 hom.)
• Consequence: JAK2 NM_004972.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.125

Genes affected

JAK2 (HGNC:6192): (Janus kinase 2) This gene encodes a non-receptor tyrosine kinase that plays a central role in cytokine and growth factor signalling. The primary isoform of this protein has an N-terminal FERM domain that is required for erythropoietin receptor association, an SH2 domain that binds STAT transcription factors, a pseudokinase domain and a C-terminal tyrosine kinase domain. Cytokine binding induces autophosphorylation and activation of this kinase. This kinase then recruits and phosphorylates signal transducer and activator of transcription (STAT) proteins. Growth factors like TGF-beta 1 also induce phosphorylation and activation of this kinase and translocation of downstream STAT proteins to the nucleus where they influence gene transcription. Mutations in this gene are associated with numerous inflammatory diseases and malignancies. This gene is a downstream target of the pleiotropic cytokine IL6 that is produced by B cells, T cells, dendritic cells and macrophages to produce an immune response or inflammation. Disregulation of the IL6/JAK2/STAT3 signalling pathways produces increased cellular proliferation and myeloproliferative neoplasms of hematopoietic stem cells. A nonsynonymous mutation in the pseudokinase domain of this gene disrupts the domains inhibitory effect and results in constitutive tyrosine phosphorylation activity and hypersensitivity to cytokine signalling. This gene and the IL6/JAK2/STAT3 signalling pathway is a therapeutic target for the treatment of excessive inflammatory responses to viral infections. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2020]

INSL6 (HGNC:6089): (insulin like 6) The protein encoded by this gene contains a classical signature of the insulin superfamily and is significantly similar to relaxin and relaxin-like factor. This gene is preferentially expressed in testis. Its expression in testis is restricted to interstitial cells surrounding seminiferous tubules, which suggests a role in sperm development and fertilization. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 9-5126321-G-GC is Benign according to our data. Variant chr9-5126321-G-GC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1319235.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00148 (225/151780) while in subpopulation NFE AF= 0.00279 (189/67650). AF 95% confidence interval is 0.00247. There are 1 homozygotes in gnomad4. There are 102 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 225 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK2	NM_004972.4	c.3178-12_3178-11insC		splice_polypyrimidine_tract_variant, intron_variant		ENST00000381652.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK2	ENST00000381652.4	c.3178-12_3178-11insC		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004972.4	P1
INSL6	ENST00000649639.1	c.*11-1811_*11-1810insG		intron_variant
JAK2	ENST00000487310.1	n.357_358insC		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 225 AN: 151662 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00233 AC: 536 AN: 230054 Hom.: 2 AF XY: 0.00234 AC XY: 291 AN XY: 124558

Gnomad AFR exome AF: 0.000198

Gnomad AMR exome AF: 0.0000339

Gnomad ASJ exome AF: 0.000659

Gnomad EAS exome AF: 0.0000582

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00198

Gnomad NFE exome AF: 0.00441

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.00242 AC: 3365 AN: 1393320 Hom.: 6 Cov.: 22 AF XY: 0.00230 AC XY: 1602 AN XY: 695366

Gnomad4 AFR exome AF: 0.000226

Gnomad4 AMR exome AF: 0.000126

Gnomad4 ASJ exome AF: 0.000241

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00268

Gnomad4 NFE exome AF: 0.00289

Gnomad4 OTH exome AF: 0.00236

GnomAD4 genome AF: 0.00148 AC: 225 AN: 151780 Hom.: 1 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74228

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00279

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00189 Hom.: 1

Bravo AF: 0.00121

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs533264615; hg19: chr9-5126321; COSMIC: COSV104700976;