8-38953341-G-T

Position:

• chr8-38953341-G-T

Variant summary

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

The NM_021623.2(PLEKHA2):​c.747G>T​(p.Lys249Asn) 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: PLEKHA2 NM_021623.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.23

Genes affected

PLEKHA2 (HGNC:14336): (pleckstrin homology domain containing A2) Enables fibronectin binding activity; laminin binding activity; and phosphatidylinositol-3,4-bisphosphate binding activity. Involved in positive regulation of cell-matrix adhesion. Located in cytoplasm and membrane. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

PLEKHA2 (HGNC:):

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
PLEKHA2	NM_021623.2	c.747G>T	p.Lys249Asn	missense_variant	9/12	ENST00000617275.5	NP_067636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHA2	ENST00000617275.5	c.747G>T	p.Lys249Asn	missense_variant	9/12	2	NM_021623.2	ENSP00000482228.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Nov 03, 2022

The c.747G>T (p.K249N) alteration is located in exon 9 (coding exon 8) of the PLEKHA2 gene. This alteration results from a G to T substitution at nucleotide position 747, causing the lysine (K) at amino acid position 249 to be replaced by an asparagine (N). 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	Pathogenic	0.92
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	.;D;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Uncertain	-0.19	T
PrimateAI	Pathogenic	0.85	D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.99	.;D;.
Vest4		0.64
MutPred		0.58		.;Loss of ubiquitination at K249 (P = 0.021);.;
MVP		0.76
ClinPred		0.94	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.55

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: chr8-38810859;