9-5126454-T-C

Variant names:

• chr9-5126454-T-C
• rs200047976
• NM_004972.4:c.3291+8T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004972.4(JAK2):​c.3291+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,421,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: JAK2 NM_004972.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002520
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.629
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 9-5126454-T-C is Benign according to our data. Variant chr9-5126454-T-C is described in ClinVar as [Benign]. Clinvar id is 2065815.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00105 (159/151146) while in subpopulation AFR AF = 0.0037 (153/41398). AF 95% confidence interval is 0.00322. There are 0 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 159 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NM_004972.4	c.3291+8T>C		splice_region_variant, intron_variant	Intron 24 of 24	ENST00000381652.4	NP_004963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4	c.3291+8T>C		splice_region_variant, intron_variant	Intron 24 of 24	1	NM_004972.4	ENSP00000371067.4
INSL6	ENST00000649639.1	c.*11-1943A>G		intron_variant	Intron 3 of 3			ENSP00000497955.1
JAK2	ENST00000487310.1	n.482+8T>C		splice_region_variant, intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 158 AN: 151028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00368

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000338 AC: 70 AN: 206880 AF XY: 0.000259

Gnomad AFR exome AF: 0.00457

Gnomad AMR exome AF: 0.0000397

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000605

GnomAD4 exome AF: 0.000114 AC: 145 AN: 1270250 Hom.: 0 Cov.: 23 AF XY: 0.0000832 AC XY: 53 AN XY: 636670

African (AFR) AF: 0.00444 AC: 127 AN: 28574

American (AMR) AF: 0.000108 AC: 4 AN: 37128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23182

East Asian (EAS) AF: 0.00 AC: 0 AN: 36892

South Asian (SAS) AF: 0.0000400 AC: 3 AN: 74978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5258

European-Non Finnish (NFE) AF: 0.00000313 AC: 3 AN: 959984

Other (OTH) AF: 0.000150 AC: 8 AN: 53270

GnomAD4 genome AF: 0.00105 AC: 159 AN: 151146 Hom.: 0 Cov.: 32 AF XY: 0.000921 AC XY: 68 AN XY: 73850

African (AFR) AF: 0.00370 AC: 153 AN: 41398

American (AMR) AF: 0.000198 AC: 3 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10504

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67378

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.000449 Hom.: 0

Bravo AF: 0.00116

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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	-0.92
CADD	Benign	0.21
DANN	Benign	0.45
PhyloP100		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.026
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: rs200047976; hg19: chr9-5126454;