8-27430997-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_173176.3(PTK2B):c.791C>A(p.Thr264Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,614,046 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (20 hom.)
• Consequence: PTK2B NM_173176.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.95

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012320578).
• BP6: Variant 8-27430997-C-A is Benign according to our data. Variant chr8-27430997-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 788820.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 529 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTK2B	NM_173176.3	c.791C>A	p.Thr264Asn	missense_variant	8/31	ENST00000346049.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTK2B	ENST00000346049.10	c.791C>A	p.Thr264Asn	missense_variant	8/31	1	NM_173176.3	A1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 529 AN: 152222 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00488

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00290 AC: 729 AN: 251238 Hom.: 5 AF XY: 0.00288 AC XY: 391 AN XY: 135776

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00428

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.000602

Gnomad NFE exome AF: 0.00426

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00428 AC: 6252 AN: 1461706 Hom.: 20 Cov.: 32 AF XY: 0.00418 AC XY: 3036 AN XY: 727156

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00463

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.000469

Gnomad4 NFE exome AF: 0.00500

Gnomad4 OTH exome AF: 0.00454

GnomAD4 genome AF: 0.00347 AC: 529 AN: 152340 Hom.: 1 Cov.: 33 AF XY: 0.00318 AC XY: 237 AN XY: 74492

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00686

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00488

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00395 Hom.: 0

Bravo AF: 0.00408

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00285 AC: 346

EpiCase AF: 0.00638

EpiControl AF: 0.00599

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Benign	0.13	T;T;.;.
Eigen	Benign	-0.066
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.81	D
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.67	N;N;N;N
REVEL	Benign	0.091
Sift	Benign	0.57	T;T;T;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.037	B;B;B;B
Vest4		0.47
MVP		0.31
MPC		0.37
ClinPred		0.012	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs61738530; hg19: chr8-27288514; COSMIC: COSV57758734; COSMIC: COSV57758734;