14-67392673-G-C

Position:

• chr14-67392673-G-C

Variant summary

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

The NM_016445.3(PLEK2):​c.658C>G​(p.Leu220Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLEK2 NM_016445.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14

Genes affected

PLEK2 (HGNC:19238): (pleckstrin 2) The protein encoded by this gene associates with membrane-bound phosphatidylinositols generated by phosphatidylinositol 3-kinase. The encoded protein then interacts with the actin cytoskeleton to induce cell spreading. In conjunction with complement component 1, q subcomponent, B chain (C1QB), this gene shows an increase in expression in melanoma cells and may serve as an accurate biomarker for the disease. [provided by RefSeq, Dec 2015]

GPHN (HGNC:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]

ACMG classification

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	Protein	UniProt
PLEK2	NM_016445.3	c.658C>G	p.Leu220Val	missense_variant	5/9	ENST00000216446.9	NP_057529.1
PLEK2	XM_047431262.1	c.658C>G	p.Leu220Val	missense_variant	5/8		XP_047287218.1
PLEK2	XM_047431263.1	c.253C>G	p.Leu85Val	missense_variant	6/10		XP_047287219.1
GPHN	XM_047430879.1	c.1312+333887G>C		intron_variant			XP_047286835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEK2	ENST00000216446.9	c.658C>G	p.Leu220Val	missense_variant	5/9	1	NM_016445.3	ENSP00000216446.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2022

The c.658C>G (p.L220V) alteration is located in exon 5 (coding exon 5) of the PLEK2 gene. This alteration results from a C to G substitution at nucleotide position 658, causing the leucine (L) at amino acid position 220 to be replaced by a valine (V). 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	0.15
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.032	D;D
Polyphen		0.97	D;.
Vest4		0.67
MutPred		0.52		Gain of catalytic residue at T218 (P = 0.0017);.;
MVP		0.76
MPC		0.85
ClinPred		0.91	D
GERP RS		4.0
Varity_R		0.23
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-67859390;