X-115122786-T-C

Position:

• chrX-115122786-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020871.4(LRCH2):​c.2074A>G​(p.Ser692Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: LRCH2 NM_020871.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.65

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRCH2	NM_020871.4	c.2074A>G	p.Ser692Gly	missense_variant	19/21	ENST00000317135.13	NP_065922.3
LRCH2	NM_001243963.2	c.2023A>G	p.Ser675Gly	missense_variant	18/20		NP_001230892.1
LRCH2	XM_006724724.4	c.2053A>G	p.Ser685Gly	missense_variant	19/21		XP_006724787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRCH2	ENST00000317135.13	c.2074A>G	p.Ser692Gly	missense_variant	19/21	1	NM_020871.4	ENSP00000325091.8
LRCH2	ENST00000538422.2	c.2023A>G	p.Ser675Gly	missense_variant	18/20	1		ENSP00000439366.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

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

Jun 02, 2023

The c.2074A>G (p.S692G) alteration is located in exon 19 (coding exon 19) of the LRCH2 gene. This alteration results from a A to G substitution at nucleotide position 2074, causing the serine (S) at amino acid position 692 to be replaced by a glycine (G). 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	0.96
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	1.9	M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.060	T;D
Sift4G	Benign	0.21	T;T
Polyphen		0.99	D;.
Vest4		0.63
MutPred		0.46		Gain of catalytic residue at S692 (P = 0.0028);.;
MVP		0.64
MPC		1.2
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.65
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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-114357349;