5-170261136-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005565.5(LCP2):c.928C>A(p.His310Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000718 in 1,601,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H310Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: LCP2 NM_005565.5 missense, splice_region
• Scores: Splicing: ADA: 0.004760
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.34

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18603131).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCP2	NM_005565.5	c.928C>A	p.His310Asn	missense_variant, splice_region_variant	14/21	ENST00000046794.10
LCP2	XM_047417171.1	c.697C>A	p.His233Asn	missense_variant, splice_region_variant	12/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCP2	ENST00000046794.10	c.928C>A	p.His310Asn	missense_variant, splice_region_variant	14/21	1	NM_005565.5	P1
LCP2	ENST00000521416.5	c.313C>A	p.His105Asn	missense_variant, splice_region_variant	6/13	2
LCP2	ENST00000520344.1	c.229C>A	p.His77Asn	missense_variant, splice_region_variant	5/8	5

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000647 AC: 16 AN: 247294 Hom.: 0 AF XY: 0.0000522 AC XY: 7 AN XY: 134148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000697 AC: 101 AN: 1449484 Hom.: 0 Cov.: 26 AF XY: 0.0000637 AC XY: 46 AN XY: 721882

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000899

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000579 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	21
Dann	Benign	0.87
DEOGEN2	Benign	0.37	T;T;T;T
Eigen	Benign	0.096
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.4	N;.;N;D
REVEL	Benign	0.12
Sift	Benign	0.23	T;.;T;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.44
MVP		0.62
MPC		0.36
ClinPred		0.12	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0048
dbscSNV1_RF	Benign	0.088
SpliceAI score (max)		0.020		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: rs200367246; hg19: chr5-169688140;