rs1808140080

Variant names:

• chr8-27397661-T-C
• rs1808140080
• NM_173176.3:c.77T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173176.3(PTK2B):​c.77T>C​(p.Met26Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M26V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PTK2B NM_173176.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.644
• Publications: 0 publications found

Genes affected

PTK2B (HGNC:9612): (protein tyrosine kinase 2 beta) This gene encodes a cytoplasmic protein tyrosine kinase which is involved in calcium-induced regulation of ion channels and activation of the map kinase signaling pathway. The encoded protein may represent an important signaling intermediate between neuropeptide-activated receptors or neurotransmitters that increase calcium flux and the downstream signals that regulate neuronal activity. The encoded protein undergoes rapid tyrosine phosphorylation and activation in response to increases in the intracellular calcium concentration, nicotinic acetylcholine receptor activation, membrane depolarization, or protein kinase C activation. This protein has been shown to bind CRK-associated substrate, nephrocystin, GTPase regulator associated with FAK, and the SH2 domain of GRB2. The encoded protein is a member of the FAK subfamily of protein tyrosine kinases but lacks significant sequence similarity to kinases from other subfamilies. Four transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1709258).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173176.3. 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
	PTK2B	NM_173176.3	MANE Select	c.77T>C	p.Met26Thr	missense	Exon 2 of 31	NP_775268.1	Q14289-1
	PTK2B	NM_004103.4		c.77T>C	p.Met26Thr	missense	Exon 3 of 32	NP_004094.3	Q14289-1
	PTK2B	NM_173174.3		c.77T>C	p.Met26Thr	missense	Exon 7 of 36	NP_775266.1	Q14289-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTK2B	ENST00000346049.10	TSL:1 MANE Select	c.77T>C	p.Met26Thr	missense	Exon 2 of 31	ENSP00000332816.6	Q14289-1
	PTK2B	ENST00000397501.5	TSL:1	c.77T>C	p.Met26Thr	missense	Exon 7 of 36	ENSP00000380638.1	Q14289-1
	PTK2B	ENST00000894137.1		c.77T>C	p.Met26Thr	missense	Exon 6 of 35	ENSP00000564196.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	0.0035	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.64
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.22		Gain of glycosylation at M26 (P = 0.0104)
MVP		0.82
MPC		0.35
ClinPred		0.28	T
GERP RS		4.7
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.51
Mutation Taster		=96/4	polymorphism

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: rs1808140080; hg19: chr8-27255178;