5-170261136-G-A

Variant names:

• chr5-170261136-G-A
• rs200367246
• NM_005565.5:c.928C>T

Variant summary

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

The NM_005565.5(LCP2):​c.928C>T​(p.His310Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,449,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LCP2 NM_005565.5 missense, splice_region
• Scores: Splicing: ADA: 0.9777
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCP2	NM_005565.5	c.928C>T	p.His310Tyr	missense_variant, splice_region_variant	Exon 14 of 21	ENST00000046794.10	NP_005556.1
LCP2	XM_047417171.1	c.697C>T	p.His233Tyr	missense_variant, splice_region_variant	Exon 12 of 19		XP_047273127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCP2	ENST00000046794.10	c.928C>T	p.His310Tyr	missense_variant, splice_region_variant	Exon 14 of 21	1	NM_005565.5	ENSP00000046794.5
LCP2	ENST00000521416.5	c.313C>T	p.His105Tyr	missense_variant, splice_region_variant	Exon 6 of 13	2		ENSP00000428871.1
LCP2	ENST00000520344.1	c.229C>T	p.His77Tyr	missense_variant, splice_region_variant	Exon 5 of 8	5		ENSP00000430391.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449484 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 721882

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 18, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LCP2 c.928C>T (p.His310Tyr) results in a conservative amino acid change in the second nucleotide of exon 14 in the encoded protein sequence adjacent to the exon 14 / intron 13 splice acceptor site. Four of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 247294 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.928C>T in individuals affected with Immunodeficiency 81 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;T;T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.1	M;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.7	N;.;N;D
REVEL	Benign	0.14
Sift	Uncertain	0.027	D;.;T;D
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.86	P;.;P;.
Vest4		0.49
MutPred		0.21		Gain of phosphorylation at H310 (P = 0.0134);Gain of phosphorylation at H310 (P = 0.0134);.;.;
MVP		0.47
MPC		0.49
ClinPred		0.71	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		0.030		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; COSMIC: COSV99253386; COSMIC: COSV99253386;