NM_173176.3:c.*1017T>C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173176.3(PTK2B):​c.*1017T>C variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 205,416 control chromosomes in the GnomAD database, including 75,877 homozygotes. 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: 𝑓 0.86 (57039 hom., cov: 33)
  • Exomes 𝑓: 0.83 (18838 hom.)
• Consequence: PTK2B NM_173176.3 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.07

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTK2B	NM_173176.3	c.*1017T>C		downstream_gene_variant		ENST00000346049.10	NP_775268.1
CHRNA2	NM_000742.4	c.*2103A>G		downstream_gene_variant		ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTK2B	ENST00000346049.10	c.*1017T>C		downstream_gene_variant		1	NM_173176.3	ENSP00000332816.6
CHRNA2	ENST00000407991.3	c.*2103A>G		downstream_gene_variant		5	NM_000742.4	ENSP00000385026.1

Frequencies

GnomAD3 genomes AF: 0.863 AC: 131189 AN: 152068 Hom.: 56991 Cov.: 33

Gnomad AFR AF: 0.898

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.827

Gnomad ASJ AF: 0.939

Gnomad EAS AF: 0.534

Gnomad SAS AF: 0.848

Gnomad FIN AF: 0.837

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.874

Gnomad OTH AF: 0.882

GnomAD4 exome AF: 0.832 AC: 44291 AN: 53228 Hom.: 18838 AF XY: 0.837 AC XY: 20794 AN XY: 24850

Gnomad4 AFR exome AF: 0.908

Gnomad4 AMR exome AF: 0.840

Gnomad4 ASJ exome AF: 0.929

Gnomad4 EAS exome AF: 0.567

Gnomad4 SAS exome AF: 0.859

Gnomad4 FIN exome AF: 0.947

Gnomad4 NFE exome AF: 0.876

Gnomad4 OTH exome AF: 0.876

GnomAD4 genome AF: 0.863 AC: 131291 AN: 152188 Hom.: 57039 Cov.: 33 AF XY: 0.857 AC XY: 63788 AN XY: 74400

Gnomad4 AFR AF: 0.898

Gnomad4 AMR AF: 0.827

Gnomad4 ASJ AF: 0.939

Gnomad4 EAS AF: 0.534

Gnomad4 SAS AF: 0.846

Gnomad4 FIN AF: 0.837

Gnomad4 NFE AF: 0.874

Gnomad4 OTH AF: 0.883

Alfa AF: 0.870 Hom.: 9745

Bravo AF: 0.865

Asia WGS AF: 0.736 AC: 2559 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.048
DANN	Benign	0.25

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs748281; hg19: chr8-27317043;