Genetic Variant LRCH2:p.Arg620His (chrX-115123183-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_020871.4(LRCH2):c.1859G>A(p.Arg620His) variant causes a missense change. The variant allele was found at a frequency of 0.000086 in 1,197,782 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 34 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 0.000072 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000087 ( 0 hom. 31 hem. )

Consequence

LRCH2
NM_020871.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.84

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14882338).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRCH2	NM_020871.4 link	c.1859G>A	p.Arg620His	missense_variant	Exon 18 of 21	ENST00000317135.13	NP_065922.3	Q5VUJ6-1
LRCH2	NM_001243963.2 link	c.1808G>A	p.Arg603His	missense_variant	Exon 17 of 20		NP_001230892.1	Q5VUJ6-2
LRCH2	XM_006724724.4 link	c.1838G>A	p.Arg613His	missense_variant	Exon 18 of 21		XP_006724787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRCH2	ENST00000317135.13 link	c.1859G>A	p.Arg620His	missense_variant	Exon 18 of 21	1	NM_020871.4	ENSP00000325091.8		Q5VUJ6-1
LRCH2	ENST00000538422.2 link	c.1808G>A	p.Arg603His	missense_variant	Exon 17 of 20	1		ENSP00000439366.1		Q5VUJ6-2

Frequencies

GnomAD3 genomes

AF:

0.0000719

AC:

AN:

111217

Hom.:

Cov.:

AF XY:

0.0000897

AC XY:

AN XY:

33455

show subpopulations

Gnomad AFR

AF:

0.0000327

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:

0.0000942

Gnomad OTH

AF:

0.00136

GnomAD3 exomes

AF:

0.0000410

AC:

AN:

170774

Hom.:

AF XY:

0.0000520

AC XY:

AN XY:

57738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000916

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000874

AC:

AN:

1086565

Hom.:

Cov.:

AF XY:

0.0000879

AC XY:

AN XY:

352751

show subpopulations

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:

0.0000387

Gnomad4 FIN exome

AF:

0.0000249

Gnomad4 NFE exome

AF:

0.000101

Gnomad4 OTH exome

AF:

0.000153

GnomAD4 genome

AF:

0.0000719

AC:

AN:

111217

Hom.:

Cov.:

AF XY:

0.0000897

AC XY:

AN XY:

33455

show subpopulations

Gnomad4 AFR

AF:

0.0000327

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:

0.0000942

Gnomad4 OTH

AF:

0.00136

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.000315

AC:

ESP6500EA

AF:

0.000312

AC:

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1859G>A (p.R620H) alteration is located in exon 18 (coding exon 18) of the LRCH2 gene. This alteration results from a G to A substitution at nucleotide position 1859, causing the arginine (R) at amino acid position 620 to be replaced by a histidine (H). 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

Uncertain

0.38

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

T;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.16

Sift

Uncertain

0.015

D;D

Sift4G

Uncertain

0.032

D;T

Polyphen

1.0

D;.

Vest4

0.26

MVP

0.17

MPC

1.5

ClinPred

0.36

GERP RS

5.2

Varity_R

0.34

gMVP

0.49

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