5-170253130-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005565.5(LCP2):c.1234G>A(p.Ala412Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,456,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: LCP2 NM_005565.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09

Genes affected

LCP2 (HGNC:6529): (lymphocyte cytosolic protein 2) This gene encodes an adapter protein that acts as a substrate of the T cell antigen receptor (TCR)-activated protein tyrosine kinase pathway. The encoded protein associates with growth factor receptor bound protein 2, and is thought to play a role TCR-mediated intracellular signal transduction. A similar protein in mouse plays a role in normal T-cell development and activation. Mice lacking this gene show subcutaneous and intraperitoneal fetal hemorrhaging, dysfunctional platelets and impaired viability. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053593487).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCP2	NM_005565.5	c.1234G>A	p.Ala412Thr	missense_variant	18/21	ENST00000046794.10
LCP2	XM_047417171.1	c.1003G>A	p.Ala335Thr	missense_variant	16/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCP2	ENST00000046794.10	c.1234G>A	p.Ala412Thr	missense_variant	18/21	1	NM_005565.5	P1
LCP2	ENST00000521416.5	c.619G>A	p.Ala207Thr	missense_variant	10/13	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000206 AC: 5 AN: 243164 Hom.: 0 AF XY: 0.0000304 AC XY: 4 AN XY: 131738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000565

Gnomad SAS exome AF: 0.0000339

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000330 AC: 48 AN: 1456344 Hom.: 0 Cov.: 29 AF XY: 0.0000345 AC XY: 25 AN XY: 724158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000587

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000298

Gnomad4 OTH exome AF: 0.0000665

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000264

ExAC AF: 0.0000166 AC: 2

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

Feb 23, 2023

The c.1234G>A (p.A412T) alteration is located in exon 18 (coding exon 18) of the LCP2 gene. This alteration results from a G to A substitution at nucleotide position 1234, causing the alanine (A) at amino acid position 412 to be replaced by a threonine (T). 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	0.065
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	10
Dann	Benign	0.90
DEOGEN2	Benign	0.37	T;T;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.054	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.46	N;.;N
REVEL	Benign	0.064
Sift	Benign	0.26	T;.;T
Sift4G	Benign	0.66	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.084
MutPred		0.24		Gain of phosphorylation at A412 (P = 0.0117);Gain of phosphorylation at A412 (P = 0.0117);.;
MVP		0.42
MPC		0.17
ClinPred		0.026	T
GERP RS		3.0
Varity_R		0.026
gMVP		0.37

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

LitVar

Other links and lift over

dbSNP: rs770608317; hg19: chr5-169680134; COSMIC: COSV50448581; COSMIC: COSV50448581;