2-68380815-G-T

Variant names:

• chr2-68380815-G-T
• rs3816281
• NM_002664.3:c.291G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002664.3(PLEK):​c.291G>T​(p.Lys97Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 1,613,520 control chromosomes in the GnomAD database, including 76,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7648 hom., cov: 32)
  • Exomes 𝑓: 0.29 (69337 hom.)
• Consequence: PLEK NM_002664.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.24
• Publications: 50 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.30253E-5).
• BP6: Variant 2-68380815-G-T is Benign according to our data. Variant chr2-68380815-G-T is described in ClinVar as Benign. ClinVar VariationId is 1258238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

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.291G>T	p.Lys97Asn	missense	Exon 3 of 9	NP_002655.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEK	ENST00000234313.8	TSL:1 MANE Select	c.291G>T	p.Lys97Asn	missense	Exon 3 of 9	ENSP00000234313.7

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45860 AN: 152000 Hom.: 7653 Cov.: 32

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.314

GnomAD2 exomes AF: 0.362 AC: 90821 AN: 251010 AF XY: 0.359

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.531

Gnomad ASJ exome AF: 0.339

Gnomad EAS exome AF: 0.705

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.256

Gnomad OTH exome AF: 0.332

GnomAD4 exome AF: 0.291 AC: 425625 AN: 1461404 Hom.: 69337 Cov.: 33 AF XY: 0.295 AC XY: 214818 AN XY: 726986

African (AFR) AF: 0.290 AC: 9691 AN: 33458

American (AMR) AF: 0.516 AC: 23050 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 8891 AN: 26122

East Asian (EAS) AF: 0.676 AC: 26821 AN: 39690

South Asian (SAS) AF: 0.482 AC: 41605 AN: 86228

European-Finnish (FIN) AF: 0.261 AC: 13915 AN: 53412

Middle Eastern (MID) AF: 0.312 AC: 1799 AN: 5764

European-Non Finnish (NFE) AF: 0.252 AC: 280618 AN: 1111660

Other (OTH) AF: 0.319 AC: 19235 AN: 60380

GnomAD4 genome AF: 0.302 AC: 45887 AN: 152116 Hom.: 7648 Cov.: 32 AF XY: 0.308 AC XY: 22944 AN XY: 74378

African (AFR) AF: 0.291 AC: 12081 AN: 41482

American (AMR) AF: 0.394 AC: 6021 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1183 AN: 3470

East Asian (EAS) AF: 0.693 AC: 3580 AN: 5168

South Asian (SAS) AF: 0.486 AC: 2344 AN: 4824

European-Finnish (FIN) AF: 0.249 AC: 2643 AN: 10602

Middle Eastern (MID) AF: 0.243 AC: 71 AN: 292

European-Non Finnish (NFE) AF: 0.249 AC: 16937 AN: 67970

Other (OTH) AF: 0.311 AC: 657 AN: 2110

Alfa AF: 0.277 Hom.: 28012

Bravo AF: 0.315

TwinsUK AF: 0.245 AC: 910

ALSPAC AF: 0.261 AC: 1005

ESP6500AA AF: 0.288 AC: 1270

ESP6500EA AF: 0.257 AC: 2211

ExAC AF: 0.354 AC: 42937

Asia WGS AF: 0.539 AC: 1872 AN: 3478

EpiCase AF: 0.258

EpiControl AF: 0.257

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.000023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.14
Sift	Benign	0.48	T
Sift4G	Benign	0.072	T
Polyphen		1.0	D
Vest4		0.23
MutPred		0.56		Loss of MoRF binding (P = 0.04)
MPC		0.36
ClinPred		0.018	T
GERP RS		4.0
Varity_R		0.28
gMVP		0.58
Mutation Taster		=84/16	polymorphism (auto)

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: rs3816281; hg19: chr2-68607947; COSMIC: COSV52250863;