X-115165647-C-A

Position:

• chrX-115165647-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_020871.4(LRCH2):​c.1207G>T​(p.Val403Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000387 in 1,033,543 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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: not found (cov: 22)
  • Exomes 𝑓: 0.0000039 (0 hom. 2 hem.)
• Consequence: LRCH2 NM_020871.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043035448).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRCH2	NM_020871.4	c.1207G>T	p.Val403Leu	missense_variant	9/21	ENST00000317135.13	NP_065922.3
LRCH2	NM_001243963.2	c.1207G>T	p.Val403Leu	missense_variant	9/20		NP_001230892.1
LRCH2	XM_006724724.4	c.1186G>T	p.Val396Leu	missense_variant	9/21		XP_006724787.2
LRCH2	XM_017029696.3	c.1207G>T	p.Val403Leu	missense_variant	9/16		XP_016885185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRCH2	ENST00000317135.13	c.1207G>T	p.Val403Leu	missense_variant	9/21	1	NM_020871.4	ENSP00000325091.8
LRCH2	ENST00000538422.2	c.1207G>T	p.Val403Leu	missense_variant	9/20	1		ENSP00000439366.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000387 AC: 4 AN: 1033543 Hom.: 0 Cov.: 25 AF XY: 0.00000619 AC XY: 2 AN XY: 323031

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: 0.0000207

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000125

Gnomad4 OTH exome AF: 0.0000458

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

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

Dec 13, 2021

The c.1207G>T (p.V403L) alteration is located in exon 9 (coding exon 9) of the LRCH2 gene. This alteration results from a G to T substitution at nucleotide position 1207, causing the valine (V) at amino acid position 403 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.84
DEOGEN2	Benign	0.052	T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-0.55	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.17	N;N
REVEL	Benign	0.036
Sift	Benign	0.74	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.0	B;.
Vest4		0.086
MutPred		0.22		Loss of disorder (P = 0.1184);Loss of disorder (P = 0.1184);
MVP		0.27
MPC		0.43
ClinPred		0.28	T
GERP RS		4.3
Varity_R		0.068
gMVP		0.072

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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

Other links and lift over

dbSNP: rs2072553218; hg19: chrX-114400210;