rs748281

Variant names:

• chr8-27459526-T-A
• rs748281
• NM_173176.3:c.*1017T>A

Your query was ambiguous. Multiple possible variants found:

• chr8-27459526-T-A
• chr8-27459526-T-C
• chr8-27459526-T-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173176.3(PTK2B):​c.*1017T>A variant causes a downstream gene 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTK2B NM_173176.3 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.07
• Publications: 10 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]

CHRNA2 (HGNC:1956): (cholinergic receptor nicotinic alpha 2 subunit) Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels formed by a pentameric arrangement of alpha and beta subunits to create distinct muscle and neuronal receptors. Neuronal receptors are found throughout the peripheral and central nervous system where they are involved in fast synaptic transmission. This gene encodes an alpha subunit that is widely expressed in the brain. The proposed structure for nAChR subunits is a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region. Mutations in this gene cause autosomal dominant nocturnal frontal lobe epilepsy type 4. Single nucleotide polymorphisms (SNPs) in this gene have been associated with nicotine dependence. [provided by RefSeq, Nov 2009]

CHRNA2 Gene-Disease associations (from GenCC):

• autosomal dominant nocturnal frontal lobe epilepsy 4

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae)
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sleep-related hypermotor epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• benign familial infantile epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.*1017T>A		downstream_gene	N/A	NP_775268.1	Q14289-1
	CHRNA2	NM_000742.4	MANE Select	c.*2103A>T		downstream_gene	N/A	NP_000733.2	Q15822-1
	PTK2B	NM_004103.4		c.*1017T>A		downstream_gene	N/A	NP_004094.3	Q14289-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTK2B	ENST00000346049.10	TSL:1 MANE Select	c.*1017T>A		downstream_gene	N/A	ENSP00000332816.6	Q14289-1
	CHRNA2	ENST00000407991.3	TSL:5 MANE Select	c.*2103A>T		downstream_gene	N/A	ENSP00000385026.1	Q15822-1
	PTK2B	ENST00000397501.5	TSL:1	c.*1017T>A		downstream_gene	N/A	ENSP00000380638.1	Q14289-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 53292 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 24874

African (AFR) AF: 0.00 AC: 0 AN: 2382

American (AMR) AF: 0.00 AC: 0 AN: 1482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 8268

South Asian (SAS) AF: 0.00 AC: 0 AN: 476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 340

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 32496

Other (OTH) AF: 0.00 AC: 0 AN: 4386

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.041
DANN	Benign	0.39
PhyloP100		-2.1

Splicing

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

Other links and lift over

dbSNP: rs748281; hg19: chr8-27317043;