8-27397592-G-A

Variant names:

• chr8-27397592-G-A
• rs1290235746
• NM_173176.3:c.8G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_173176.3(PTK2B):​c.8G>A​(p.Gly3Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PTK2B NM_173176.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33704817).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

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.8G>A	p.Gly3Glu	missense	Exon 2 of 31	NP_775268.1	Q14289-1
	PTK2B	NM_004103.4		c.8G>A	p.Gly3Glu	missense	Exon 3 of 32	NP_004094.3	Q14289-1
	PTK2B	NM_173174.3		c.8G>A	p.Gly3Glu	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.8G>A	p.Gly3Glu	missense	Exon 2 of 31	ENSP00000332816.6	Q14289-1
	PTK2B	ENST00000397501.5	TSL:1	c.8G>A	p.Gly3Glu	missense	Exon 7 of 36	ENSP00000380638.1	Q14289-1
	PTK2B	ENST00000894137.1		c.8G>A	p.Gly3Glu	missense	Exon 6 of 35	ENSP00000564196.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251256 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461362 Hom.: 0 Cov.: 45 AF XY: 0.00000688 AC XY: 5 AN XY: 726976

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5368

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000468 Hom.: 0

ClinVar

ClinVar submissions

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	0.18
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.018	D
Polyphen		0.96	D
Vest4		0.38
MutPred		0.18		Loss of MoRF binding (P = 0.0141)
MVP		0.72
MPC		0.45
ClinPred		0.73	D
GERP RS		4.8
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.40
Mutation Taster		=86/14	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: rs1290235746; hg19: chr8-27255109;