X-115113290-C-T

Variant names:

• chrX-115113290-C-T
• NM_020871.4:c.2224G>A

Variant summary

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

The NM_020871.4(LRCH2):​c.2224G>A​(p.Val742Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000922 in 1,084,458 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: LRCH2 NM_020871.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.18

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.2224G>A	p.Val742Met	missense_variant	Exon 21 of 21	ENST00000317135.13	NP_065922.3
LRCH2	NM_001243963.2	c.2173G>A	p.Val725Met	missense_variant	Exon 20 of 20		NP_001230892.1
LRCH2	XM_006724724.4	c.2203G>A	p.Val735Met	missense_variant	Exon 21 of 21		XP_006724787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRCH2	ENST00000317135.13	c.2224G>A	p.Val742Met	missense_variant	Exon 21 of 21	1	NM_020871.4	ENSP00000325091.8
LRCH2	ENST00000538422.2	c.2173G>A	p.Val725Met	missense_variant	Exon 20 of 20	1		ENSP00000439366.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.22e-7 AC: 1 AN: 1084458 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 353414

Gnomad4 AFR exome AF: 0.0000382

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: 0.00

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

Apr 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2224G>A (p.V742M) alteration is located in exon 21 (coding exon 21) of the LRCH2 gene. This alteration results from a G to A substitution at nucleotide position 2224, causing the valine (V) at amino acid position 742 to be replaced by a methionine (M). 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	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.72	N;N
REVEL	Pathogenic	0.70
Sift	Benign	0.23	T;T
Sift4G	Benign	0.16	T;T
Polyphen		1.0	D;.
Vest4		0.49
MutPred		0.69		Loss of methylation at K743 (P = 0.0228);.;
MVP		0.86
MPC		1.3
ClinPred		0.88	D
GERP RS		5.5
Varity_R		0.25
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-114347853;