Variant X-115130190-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_020871.4(LRCH2):c.1705A>G(p.Met569Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000363 in 1,020,206 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 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 0.000072 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000032 ( 0 hom. 7 hem. )

Consequence

LRCH2
NM_020871.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.54

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04020828).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRCH2	NM_020871.4 linkuse as main transcript	c.1705A>G	p.Met569Val	missense_variant	15/21	ENST00000317135.13	NP_065922.3	Q5VUJ6-1
LRCH2	NM_001243963.2 linkuse as main transcript	c.1705A>G	p.Met569Val	missense_variant	15/20		NP_001230892.1	Q5VUJ6-2
LRCH2	XM_006724724.4 linkuse as main transcript	c.1684A>G	p.Met562Val	missense_variant	15/21		XP_006724787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRCH2	ENST00000317135.13 linkuse as main transcript	c.1705A>G	p.Met569Val	missense_variant	15/21	1	NM_020871.4	ENSP00000325091.8		Q5VUJ6-1
LRCH2	ENST00000538422.2 linkuse as main transcript	c.1705A>G	p.Met569Val	missense_variant	15/20	1		ENSP00000439366.1		Q5VUJ6-2

Frequencies

GnomAD3 genomes

AF:

0.0000716

AC:

AN:

111742

Hom.:

Cov.:

AF XY:

0.0000590

AC XY:

AN XY:

33906

show subpopulations

Gnomad AFR

AF:

0.0000324

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

125436

Hom.:

AF XY:

0.00

AC XY:

AN XY:

31640

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:

0.0000351

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000319

AC:

AN:

908464

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

253470

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000404

Gnomad4 OTH exome

AF:

0.0000258

GnomAD4 genome

AF:

0.0000716

AC:

AN:

111742

Hom.:

Cov.:

AF XY:

0.0000590

AC XY:

AN XY:

33906

show subpopulations

Gnomad4 AFR

AF:

0.0000324

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:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000853

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 17, 2021

The c.1705A>G (p.M569V) alteration is located in exon 15 (coding exon 15) of the LRCH2 gene. This alteration results from a A to G substitution at nucleotide position 1705, causing the methionine (M) at amino acid position 569 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

0.071

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.060

T;.

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.84

T;D

M_CAP

Benign

0.054

MetaRNN

Benign

0.040

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.12

N;N

REVEL

Benign

0.045

Sift

Benign

0.50

T;T

Sift4G

Benign

0.60

T;T

Polyphen

0.0

B;.

Vest4

0.10

MVP

0.20

MPC

0.45

ClinPred

0.026

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.19

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