8-27422366-G-A

Position:

• chr8-27422366-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The ENST00000346049.10(PTK2B):​c.534G>A​(p.Leu178=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,613,190 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L178L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0098 (26 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (15 hom.)
• Consequence: PTK2B ENST00000346049.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.79

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 8-27422366-G-A is Benign according to our data. Variant chr8-27422366-G-A is described in ClinVar as [Benign]. Clinvar id is 773403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00979 (1492/152372) while in subpopulation AFR AF= 0.0335 (1392/41582). AF 95% confidence interval is 0.032. There are 26 homozygotes in gnomad4. There are 685 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1492 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTK2B	NM_173176.3	c.534G>A	p.Leu178=	synonymous_variant	5/31	ENST00000346049.10	NP_775268.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTK2B	ENST00000346049.10	c.534G>A	p.Leu178=	synonymous_variant	5/31	1	NM_173176.3	ENSP00000332816	A1

Frequencies

GnomAD3 genomes AF: 0.00980 AC: 1492 AN: 152254 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.00268 AC: 667 AN: 248588 Hom.: 4 AF XY: 0.00174 AC XY: 234 AN XY: 134438

Gnomad AFR exome AF: 0.0369

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000806

Gnomad OTH exome AF: 0.000823

GnomAD4 exome AF: 0.000955 AC: 1395 AN: 1460818 Hom.: 15 Cov.: 30 AF XY: 0.000823 AC XY: 598 AN XY: 726704

Gnomad4 AFR exome AF: 0.0331

Gnomad4 AMR exome AF: 0.00198

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00979 AC: 1492 AN: 152372 Hom.: 26 Cov.: 33 AF XY: 0.00919 AC XY: 685 AN XY: 74512

Gnomad4 AFR AF: 0.0335

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00369 Hom.: 6

Bravo AF: 0.0112

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000594

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 24, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.6
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11991368; hg19: chr8-27279883;