X-115165930-C-T

Position:

• chrX-115165930-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000317135.13(LRCH2):​c.1109G>A​(p.Ser370Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000572 in 1,048,539 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000057 (0 hom. 2 hem.)
• Consequence: LRCH2 ENST00000317135.13 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.11

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 -4 ACMG points.

• 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.1109G>A	p.Ser370Asn	missense_variant	8/21	ENST00000317135.13	NP_065922.3
LRCH2	NM_001243963.2	c.1109G>A	p.Ser370Asn	missense_variant	8/20		NP_001230892.1
LRCH2	XM_006724724.4	c.1109G>A	p.Ser370Asn	missense_variant	8/21		XP_006724787.2
LRCH2	XM_017029696.3	c.1109G>A	p.Ser370Asn	missense_variant	8/16		XP_016885185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRCH2	ENST00000317135.13	c.1109G>A	p.Ser370Asn	missense_variant	8/21	1	NM_020871.4	ENSP00000325091	P2
LRCH2	ENST00000538422.2	c.1109G>A	p.Ser370Asn	missense_variant	8/20	1		ENSP00000439366	A2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000572 AC: 6 AN: 1048539 Hom.: 0 Cov.: 28 AF XY: 0.00000593 AC XY: 2 AN XY: 337271

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: 0.00000737

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

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

Feb 16, 2023

The c.1109G>A (p.S370N) alteration is located in exon 8 (coding exon 8) of the LRCH2 gene. This alteration results from a G to A substitution at nucleotide position 1109, causing the serine (S) at amino acid position 370 to be replaced by an asparagine (N). 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	0.67
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.096
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.044	D;T
Polyphen		0.11	B;.
Vest4		0.49
MutPred		0.25		Gain of catalytic residue at S370 (P = 0.0055);Gain of catalytic residue at S370 (P = 0.0055);
MVP		0.62
MPC		1.3
ClinPred		0.90	D
GERP RS		5.7
Varity_R		0.69
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-114400493;