X-115149886-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_020871.4(LRCH2):c.1636A>G(p.Ile546Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000083 in 1,205,183 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000064 ( 0 hom. 2 hem. )

Consequence

LRCH2
NM_020871.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.626

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026179463).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRCH2	NM_020871.4 link	c.1636A>G	p.Ile546Val	missense_variant	Exon 14 of 21	ENST00000317135.13	NP_065922.3	Q5VUJ6-1
LRCH2	NM_001243963.2 link	c.1636A>G	p.Ile546Val	missense_variant	Exon 14 of 20		NP_001230892.1	Q5VUJ6-2
LRCH2	XM_006724724.4 link	c.1615A>G	p.Ile539Val	missense_variant	Exon 14 of 21		XP_006724787.2
LRCH2	XM_017029696.3 link	c.1636A>G	p.Ile546Val	missense_variant	Exon 14 of 16		XP_016885185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRCH2	ENST00000317135.13 link	c.1636A>G	p.Ile546Val	missense_variant	Exon 14 of 21	1	NM_020871.4	ENSP00000325091.8		Q5VUJ6-1
LRCH2	ENST00000538422.2 link	c.1636A>G	p.Ile546Val	missense_variant	Exon 14 of 20	1		ENSP00000439366.1		Q5VUJ6-2

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111733

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33949

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000841

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000112

AC:

AN:

178361

Hom.:

AF XY:

0.00

AC XY:

AN XY:

64745

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000150

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000640

AC:

AN:

1093450

Hom.:

Cov.:

AF XY:

0.00000556

AC XY:

AN XY:

359834

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000200

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111733

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33949

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000841

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1636A>G (p.I546V) alteration is located in exon 14 (coding exon 14) of the LRCH2 gene. This alteration results from a A to G substitution at nucleotide position 1636, causing the isoleucine (I) at amino acid position 546 to be replaced by a valine (V). 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

0.053

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.046

T;.

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.067

MetaRNN

Benign

0.026

T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

-0.26

N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.030

N;N

REVEL

Benign

0.056

Sift

Benign

0.82

T;T

Sift4G

Benign

0.60

T;T

Polyphen

0.0010

B;.

Vest4

0.067

MutPred

0.20

Gain of MoRF binding (P = 0.1136);Gain of MoRF binding (P = 0.1136);

MVP

0.13

MPC

0.37

ClinPred

0.080

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.073

gMVP

0.076

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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