2-68386533-C-G

Variant names:

• chr2-68386533-C-G
• rs182137525
• NM_002664.3:c.504C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002664.3(PLEK):​c.504C>G​(p.Asn168Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLEK NM_002664.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.284
• Publications: 0 publications found

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]

ENSG00000301281 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09652573).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002664.3. 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
	PLEK	NM_002664.3	MANE Select	c.504C>G	p.Asn168Lys	missense	Exon 5 of 9	NP_002655.2	P08567

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEK	ENST00000234313.8	TSL:1 MANE Select	c.504C>G	p.Asn168Lys	missense	Exon 5 of 9	ENSP00000234313.7	P08567
	ENSG00000301281	ENST00000777616.1		n.189-3755G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461460 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727056

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111694

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.6
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L
PhyloP100		0.28
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.087
Sift	Benign	0.47	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	B
Vest4		0.072
MutPred		0.72		Gain of methylation at N168 (P = 0.023)
MVP		0.38
MPC		0.060
ClinPred		0.083	T
GERP RS		0.71
Varity_R		0.042
gMVP		0.40
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs182137525; hg19: chr2-68613665;