chrX-115126866-T-C

Position:

• chrX-115126866-T-C

Variant summary

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

The ENST00000317135.13(LRCH2):​c.1768A>G​(p.Thr590Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 973,812 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 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. T590I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000021 (0 hom. 0 hem.)
• Consequence: LRCH2 ENST00000317135.13 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

Genes affected

LRCH2 (HGNC:29292): (leucine rich repeats and calponin homology domain containing 2) This gene encodes a member of the leucine-rich repeat and calponin homology domain-containing protein family. These family members contain multiple N-terminal leucine-rich repeats, in addition to a C-terminal calponin homology domain, a type of domain that mediates interactions with actin filaments. These proteins are conserved across animal species, and studies of a similar Drosophila protein indicate a function as a cytoskeletal scaffolding protein. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2011]

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=0.04092464).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRCH2	NM_020871.4	c.1768A>G	p.Thr590Ala	missense_variant	16/21	ENST00000317135.13	NP_065922.3
LRCH2	XM_006724724.4	c.1747A>G	p.Thr583Ala	missense_variant	16/21		XP_006724787.2
LRCH2	NM_001243963.2	c.1741-2864A>G		intron_variant			NP_001230892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRCH2	ENST00000317135.13	c.1768A>G	p.Thr590Ala	missense_variant	16/21	1	NM_020871.4	ENSP00000325091	P2
LRCH2	ENST00000538422.2	c.1741-2864A>G		intron_variant		1		ENSP00000439366	A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000205 AC: 2 AN: 973812 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 295138

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: 0.00

Gnomad4 NFE exome AF: 0.00000257

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

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

Mar 25, 2024

The c.1768A>G (p.T590A) alteration is located in exon 16 (coding exon 16) of the LRCH2 gene. This alteration results from a A to G substitution at nucleotide position 1768, causing the threonine (T) at amino acid position 590 to be replaced by an alanine (A). 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	0.062
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.079	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.089	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.58	N
REVEL	Benign	0.21
Sift	Benign	0.94	T
Sift4G	Benign	0.99	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.14		Loss of glycosylation at T590 (P = 0.0047);
MVP		0.18
MPC		0.43
ClinPred		0.042	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.041
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1556528301; hg19: chrX-114361429;