15-74799319-A-T

Variant names:

• chr15-74799319-A-T
• rs750380440
• NM_004383.3:c.290A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004383.3(CSK):​c.290A>T​(p.Tyr97Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y97H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CSK NM_004383.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.97
• Publications: 1 publications found

Genes affected

CSK (HGNC:2444): (C-terminal Src kinase) The protein encoded by this gene is involved in multiple pathways, including the regulation of Src family kinases. It plays an important role in T-cell activation through its association with the protein encoded by the protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene. This protein also phosphorylates C-terminal tyrosine residues on multiple substrates, including the protein encoded by the SRC proto-oncogene, non-receptor tyrosine kinase gene. Phosphorylation suppresses the kinase activity of the Src family tyrosine kinases. An intronic polymorphism (rs34933034) in this gene has been found to affect B-cell activation and is associated with systemic lupus erythematosus (SLE). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004383.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSK	NM_004383.3	MANE Select	c.290A>T	p.Tyr97Phe	missense	Exon 5 of 13	NP_004374.1	B2R6Q4
	CSK	NM_001127190.2		c.290A>T	p.Tyr97Phe	missense	Exon 6 of 14	NP_001120662.1	P41240
	CSK	NM_001354988.2		c.290A>T	p.Tyr97Phe	missense	Exon 7 of 15	NP_001341917.1	P41240

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSK	ENST00000220003.14	TSL:1 MANE Select	c.290A>T	p.Tyr97Phe	missense	Exon 5 of 13	ENSP00000220003.9	P41240
	CSK	ENST00000439220.6	TSL:2	c.290A>T	p.Tyr97Phe	missense	Exon 6 of 14	ENSP00000414764.2	P41240
	CSK	ENST00000567571.5	TSL:2	c.290A>T	p.Tyr97Phe	missense	Exon 7 of 15	ENSP00000454906.1	P41240

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.053
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.83	L
PhyloP100		5.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.93	N
REVEL	Uncertain	0.30
Sift	Benign	0.57	T
Sift4G	Benign	0.68	T
Polyphen		0.012	B
Vest4		0.32
MutPred		0.36		Loss of phosphorylation at Y97 (P = 0.1636)
MVP		0.74
MPC		1.2
ClinPred		0.56	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: 11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs750380440; hg19: chr15-75091660;