Variant 2-68380891-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002664.3(PLEK):c.367A>C(p.Thr123Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,296 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PLEK
NM_002664.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.77

Variant links:

Genes affected

PLEK (HGNC:9070): (pleckstrin) Enables phosphatidylinositol-3,4-bisphosphate binding activity; protein homodimerization activity; and protein kinase C binding activity. Involved in several processes, including G protein-coupled receptor signaling pathway; actin cytoskeleton organization; and positive regulation of supramolecular fiber organization. Located in cytoplasm and ruffle membrane. [provided by Alliance of Genome Resources, Apr 2022]

PLEK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEK	NM_002664.3 linkuse as main transcript	c.367A>C	p.Thr123Pro	missense_variant	3/9	ENST00000234313.8
PLEK	XM_047444772.1 linkuse as main transcript	c.367A>C	p.Thr123Pro	missense_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEK	ENST00000234313.8 linkuse as main transcript	c.367A>C	p.Thr123Pro	missense_variant	3/9	1	NM_002664.3	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250714

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135514

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461296

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726966

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2023

The c.367A>C (p.T123P) alteration is located in exon 3 (coding exon 3) of the PLEK gene. This alteration results from a A to C substitution at nucleotide position 367, causing the threonine (T) at amino acid position 123 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.78

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.60

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.5

REVEL

Benign

0.14

Sift

Benign

0.085

Sift4G

Benign

0.074

Polyphen

0.69

Vest4

0.54

MutPred

0.44

Loss of MoRF binding (P = 0.0673);

MVP

0.88

MPC

0.22

ClinPred

0.71

GERP RS

5.8

Varity_R

0.41

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over