8-27459526-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004103.4(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_004103.4 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

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004103.4. 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>C		downstream_gene	N/A	NP_775268.1
	CHRNA2	NM_000742.4	MANE Select	c.*2103A>G		downstream_gene	N/A	NP_000733.2
	PTK2B	NM_004103.4		c.*1017T>C		downstream_gene	N/A	NP_004094.3

Ensembl Transcripts

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

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

African (AFR) AF: 0.908 AC: 2163 AN: 2382

American (AMR) AF: 0.840 AC: 1243 AN: 1480

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 3178 AN: 3422

East Asian (EAS) AF: 0.567 AC: 4681 AN: 8256

South Asian (SAS) AF: 0.859 AC: 409 AN: 476

European-Finnish (FIN) AF: 0.947 AC: 36 AN: 38

Middle Eastern (MID) AF: 0.950 AC: 323 AN: 340

European-Non Finnish (NFE) AF: 0.876 AC: 28423 AN: 32456

Other (OTH) AF: 0.876 AC: 3835 AN: 4378

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

African (AFR) AF: 0.898 AC: 37284 AN: 41532

American (AMR) AF: 0.827 AC: 12655 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.939 AC: 3259 AN: 3472

East Asian (EAS) AF: 0.534 AC: 2754 AN: 5156

South Asian (SAS) AF: 0.846 AC: 4075 AN: 4814

European-Finnish (FIN) AF: 0.837 AC: 8865 AN: 10596

Middle Eastern (MID) AF: 0.942 AC: 277 AN: 294

European-Non Finnish (NFE) AF: 0.874 AC: 59423 AN: 68002

Other (OTH) AF: 0.883 AC: 1868 AN: 2116

Alfa AF: 0.871 Hom.: 10056

Bravo AF: 0.865

Asia WGS AF: 0.736 AC: 2559 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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