chrX-115188356-G-A

Position:

• chrX-115188356-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000317135.13(LRCH2):​c.364C>T​(p.Arg122Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000487 in 1,179,173 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 166 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 0.00037 (0 hom., 9 hem., cov: 24)
  • Exomes 𝑓: 0.00050 (0 hom. 157 hem.)
• Consequence: LRCH2 ENST00000317135.13 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2325261).
• BS2: High Hemizygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRCH2	NM_020871.4	c.364C>T	p.Arg122Cys	missense_variant	2/21	ENST00000317135.13	NP_065922.3
LRCH2	NM_001243963.2	c.364C>T	p.Arg122Cys	missense_variant	2/20		NP_001230892.1
LRCH2	XM_006724724.4	c.364C>T	p.Arg122Cys	missense_variant	2/21		XP_006724787.2
LRCH2	XM_017029696.3	c.364C>T	p.Arg122Cys	missense_variant	2/16		XP_016885185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRCH2	ENST00000317135.13	c.364C>T	p.Arg122Cys	missense_variant	2/21	1	NM_020871.4	ENSP00000325091	P2
LRCH2	ENST00000538422.2	c.364C>T	p.Arg122Cys	missense_variant	2/20	1		ENSP00000439366	A2

Frequencies

GnomAD3 genomes AF: 0.000367 AC: 41 AN: 111630 Hom.: 0 Cov.: 24 AF XY: 0.000266 AC XY: 9 AN XY: 33852

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000190

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: 0.000583

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000346 AC: 51 AN: 147320 Hom.: 0 AF XY: 0.000364 AC XY: 15 AN XY: 41170

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000523

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000685

Gnomad NFE exome AF: 0.000549

Gnomad OTH exome AF: 0.000569

GnomAD4 exome AF: 0.000499 AC: 533 AN: 1067486 Hom.: 0 Cov.: 25 AF XY: 0.000462 AC XY: 157 AN XY: 339902

Gnomad4 AFR exome AF: 0.0000395

Gnomad4 AMR exome AF: 0.000458

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000251

Gnomad4 NFE exome AF: 0.000589

Gnomad4 OTH exome AF: 0.000668

GnomAD4 genome AF: 0.000367 AC: 41 AN: 111687 Hom.: 0 Cov.: 24 AF XY: 0.000265 AC XY: 9 AN XY: 33919

Gnomad4 AFR AF: 0.000195

Gnomad4 AMR AF: 0.000190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000583

Gnomad4 OTH AF: 0.00132

Alfa AF: 0.000170 Hom.: 2

Bravo AF: 0.000525

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000332 AC: 1

ESP6500EA AF: 0.000945 AC: 6

ExAC AF: 0.000415 AC: 50

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

Jul 07, 2022

The c.364C>T (p.R122C) alteration is located in exon 2 (coding exon 2) of the LRCH2 gene. This alteration results from a C to T substitution at nucleotide position 364, causing the arginine (R) at amino acid position 122 to be replaced by a cysteine (C). 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	0.94
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.55
MVP		0.59
MPC		1.5
ClinPred		0.23	T
GERP RS		4.8
Varity_R		0.81
gMVP		0.50

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

Other links and lift over

dbSNP: rs373246698; hg19: chrX-114422919; COSMIC: COSV57750564; COSMIC: COSV57750564;