rs397514260

Variant names:

• chr5-157248980-C-G
• rs397514260
• NM_005546.4:c.1764C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-157248980-C-G
• chr5-157248980-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_005546.4(ITK):​c.1764C>G​(p.Tyr588*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ITK NM_005546.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.58
• Publications: 7 publications found

Genes affected

ITK (HGNC:6171): (IL2 inducible T cell kinase) This gene encodes an intracellular tyrosine kinase expressed in T-cells. The protein contains both SH2 and SH3 domains which are often found in intracellular kinases. It is thought to play a role in T-cell proliferation and differentiation. [provided by RefSeq, Jul 2008]

ITK Gene-Disease associations (from GenCC):

• lymphoproliferative syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• lymphoproliferative syndrome 1

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0531 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-157248980-C-G is Pathogenic according to our data. Variant chr5-157248980-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 64371.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITK	NM_005546.4	c.1764C>G	p.Tyr588*	stop_gained	Exon 16 of 17	ENST00000422843.8	NP_005537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITK	ENST00000422843.8	c.1764C>G	p.Tyr588*	stop_gained	Exon 16 of 17	1	NM_005546.4	ENSP00000398655.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lymphoproliferative syndrome 1 Pathogenic:1

May 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		1.6
Vest4		0.92
GERP RS		3.6
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs397514260; hg19: chr5-156675990;