X-115122768-G-A

Position:

chrX-115122768-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP4_ModerateBS2

The ENST00000317135.13(LRCH2):c.2092C>T(p.Pro698Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000885 in 1,208,448 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 343 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., 18 hem., cov: 23)

Exomes 𝑓: 0.00089 ( 0 hom. 325 hem. )

Consequence

LRCH2
ENST00000317135.13 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.70

Variant links:

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]

LRCH2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, M_CAP, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.09547421).

BS2

High Hemizygotes in GnomAd4 at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LRCH2	NM_020871.4 linkuse as main transcript	c.2092C>T	p.Pro698Ser	missense_variant	19/21	ENST00000317135.13	NP_065922.3
LRCH2	NM_001243963.2 linkuse as main transcript	c.2041C>T	p.Pro681Ser	missense_variant	18/20		NP_001230892.1
LRCH2	XM_006724724.4 linkuse as main transcript	c.2071C>T	p.Pro691Ser	missense_variant	19/21		XP_006724787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRCH2	ENST00000317135.13 linkuse as main transcript	c.2092C>T	p.Pro698Ser	missense_variant	19/21	1	NM_020871.4	ENSP00000325091	P2	Q5VUJ6-1
LRCH2	ENST00000538422.2 linkuse as main transcript	c.2041C>T	p.Pro681Ser	missense_variant	18/20	1		ENSP00000439366	A2	Q5VUJ6-2

Frequencies

GnomAD3 genomes

AF:

0.000797

AC:

AN:

111674

Hom.:

Cov.:

AF XY:

0.000532

AC XY:

AN XY:

33852

show subpopulations

Gnomad AFR

AF:

0.000163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00158

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000646

AC:

115

AN:

178145

Hom.:

AF XY:

0.000637

AC XY:

AN XY:

64397

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000744

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000224

Gnomad FIN exome

AF:

0.000126

Gnomad NFE exome

AF:

0.00131

Gnomad OTH exome

AF:

0.000456

GnomAD4 exome

AF:

0.000894

AC:

981

AN:

1096722

Hom.:

Cov.:

AF XY:

0.000897

AC XY:

325

AN XY:

362292

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000168

Gnomad4 FIN exome

AF:

0.000173

Gnomad4 NFE exome

AF:

0.00110

Gnomad4 OTH exome

AF:

0.000673

GnomAD4 genome

AF:

0.000797

AC:

AN:

111726

Hom.:

Cov.:

AF XY:

0.000531

AC XY:

AN XY:

33914

show subpopulations

Gnomad4 AFR

AF:

0.000162

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00158

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00123

Hom.:

Bravo

AF:

0.000816

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00173

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00109

AC:

ExAC

AF:

0.000629

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.2092C>T (p.P698S) alteration is located in exon 19 (coding exon 19) of the LRCH2 gene. This alteration results from a C to T substitution at nucleotide position 2092, causing the proline (P) at amino acid position 698 to be replaced by a serine (S). 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

0.99

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.095

T;T

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.2

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-6.6

D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.028

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.70

P;.

Vest4

0.23

MVP

0.61

MPC

1.2

ClinPred

0.16

GERP RS

4.5

Varity_R

0.56

gMVP

0.78

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over