X-115165853-C-A

Variant names:

• chrX-115165853-C-A
• NM_020871.4:c.1186G>T

Variant summary

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

The NM_020871.4(LRCH2):​c.1186G>T​(p.Asp396Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000193 in 1,034,843 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: LRCH2 NM_020871.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.74

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 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
LRCH2	NM_020871.4	c.1186G>T	p.Asp396Tyr	missense_variant	Exon 8 of 21	ENST00000317135.13	NP_065922.3
LRCH2	NM_001243963.2	c.1186G>T	p.Asp396Tyr	missense_variant	Exon 8 of 20		NP_001230892.1
LRCH2	XM_017029696.3	c.1186G>T	p.Asp396Tyr	missense_variant	Exon 8 of 16		XP_016885185.1
LRCH2	XM_006724724.4	c.1177+9G>T		intron_variant	Intron 8 of 20		XP_006724787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRCH2	ENST00000317135.13	c.1186G>T	p.Asp396Tyr	missense_variant	Exon 8 of 21	1	NM_020871.4	ENSP00000325091.8
LRCH2	ENST00000538422.2	c.1186G>T	p.Asp396Tyr	missense_variant	Exon 8 of 20	1		ENSP00000439366.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000193 AC: 2 AN: 1034843 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 327385

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: 0.00000248

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 30, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1186G>T (p.D396Y) alteration is located in exon 8 (coding exon 8) of the LRCH2 gene. This alteration results from a G to T substitution at nucleotide position 1186, causing the aspartic acid (D) at amino acid position 396 to be replaced by a tyrosine (Y). 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	0.21
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.6	L;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.21
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.014	B;.
Vest4		0.45
MutPred		0.17		Loss of ubiquitination at K394 (P = 0.0665);Loss of ubiquitination at K394 (P = 0.0665);
MVP		0.44
MPC		1.4
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.69
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.41		Position offset: 9

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: chrX-114400416;