chrX-115156614-T-A

Variant names:

• chrX-115156614-T-A
• NM_020871.4:c.1517A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020871.4(LRCH2):​c.1517A>T​(p.Glu506Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: LRCH2 NM_020871.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRCH2	NM_020871.4	c.1517A>T	p.Glu506Val	missense_variant	Exon 12 of 21	ENST00000317135.13	NP_065922.3
LRCH2	NM_001243963.2	c.1517A>T	p.Glu506Val	missense_variant	Exon 12 of 20		NP_001230892.1
LRCH2	XM_006724724.4	c.1496A>T	p.Glu499Val	missense_variant	Exon 12 of 21		XP_006724787.2
LRCH2	XM_017029696.3	c.1517A>T	p.Glu506Val	missense_variant	Exon 12 of 16		XP_016885185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRCH2	ENST00000317135.13	c.1517A>T	p.Glu506Val	missense_variant	Exon 12 of 21	1	NM_020871.4	ENSP00000325091.8
LRCH2	ENST00000538422.2	c.1517A>T	p.Glu506Val	missense_variant	Exon 12 of 20	1		ENSP00000439366.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 07, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1517A>T (p.E506V) alteration is located in exon 12 (coding exon 12) of the LRCH2 gene. This alteration results from a A to T substitution at nucleotide position 1517, causing the glutamic acid (E) at amino acid position 506 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	0.097
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T;.
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.24	T;T
Polyphen		0.18	B;.
Vest4		0.23
MutPred		0.28		Loss of ubiquitination at K502 (P = 0.0149);Loss of ubiquitination at K502 (P = 0.0149);
MVP		0.74
MPC		0.52
ClinPred		0.34	T
GERP RS		3.7
Varity_R		0.22
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.45		Position offset: 2
DS_DL_spliceai		0.47		Position offset: -12

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-114391177;