NM_020871.4:c.2224G>A

Variant names:

• chrX-115113290-C-T
• NM_020871.4:c.2224G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020871.4(LRCH2):​c.2224G>A​(p.Val742Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000922 in 1,084,458 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: LRCH2 NM_020871.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.18
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020871.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRCH2	NM_020871.4	MANE Select	c.2224G>A	p.Val742Met	missense	Exon 21 of 21	NP_065922.3
	LRCH2	NM_001243963.2		c.2173G>A	p.Val725Met	missense	Exon 20 of 20	NP_001230892.1	Q5VUJ6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRCH2	ENST00000317135.13	TSL:1 MANE Select	c.2224G>A	p.Val742Met	missense	Exon 21 of 21	ENSP00000325091.8	Q5VUJ6-1
	LRCH2	ENST00000538422.2	TSL:1	c.2173G>A	p.Val725Met	missense	Exon 20 of 20	ENSP00000439366.1	Q5VUJ6-2
	LRCH2	ENST00000857824.1		c.2203G>A	p.Val735Met	missense	Exon 21 of 21	ENSP00000527883.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.22e-7 AC: 1 AN: 1084458 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 353414

African (AFR) AF: 0.0000382 AC: 1 AN: 26195

American (AMR) AF: 0.00 AC: 0 AN: 34839

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19046

East Asian (EAS) AF: 0.00 AC: 0 AN: 29989

South Asian (SAS) AF: 0.00 AC: 0 AN: 51490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40003

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4071

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 833381

Other (OTH) AF: 0.00 AC: 0 AN: 45444

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.72	N
REVEL	Pathogenic	0.70
Sift	Benign	0.23	T
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.49
MutPred		0.69		Loss of methylation at K743 (P = 0.0228)
MVP		0.86
MPC		1.3
ClinPred		0.88	D
GERP RS		5.5
Varity_R		0.25
gMVP		0.74
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chrX-114347853;