9-5029893-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004972.4(JAK2):c.337C>G(p.Leu113Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000938 in 1,607,494 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00097 (1 hom.)
• Consequence: JAK2 NM_004972.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.31

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:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03725797).
• BP6: Variant 9-5029893-C-G is Benign according to our data. Variant chr9-5029893-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2052244.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-5029893-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000637 (97/152340) while in subpopulation NFE AF= 0.00113 (77/68028). AF 95% confidence interval is 0.000928. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 97 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK2	NM_004972.4	c.337C>G	p.Leu113Val	missense_variant	4/25	ENST00000381652.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK2	ENST00000381652.4	c.337C>G	p.Leu113Val	missense_variant	4/25	1	NM_004972.4	P1
JAK2	ENST00000636127.1	c.337C>G	p.Leu113Val	missense_variant	4/16	5

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000632 AC: 155 AN: 245224 Hom.: 0 AF XY: 0.000634 AC XY: 84 AN XY: 132528

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.000502

GnomAD4 exome AF: 0.000970 AC: 1411 AN: 1455154 Hom.: 1 Cov.: 29 AF XY: 0.000941 AC XY: 681 AN XY: 723886

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.000185

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74484

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000846 Hom.: 0

Bravo AF: 0.000771

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.000634 AC: 77

EpiCase AF: 0.000716

EpiControl AF: 0.00126

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	20
Dann	Benign	0.91
Eigen	Benign	-0.10
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.46	T
Polyphen		0.0020	.;B
Vest4		0.53
MVP		0.71
MPC		0.19
ClinPred		0.017	T
GERP RS		6.0
Varity_R		0.21
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs143103233; hg19: chr9-5029893;