NM_020871.4:c.1733A>T

Variant names:

• chrX-115130162-T-A
• NM_020871.4:c.1733A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_020871.4(LRCH2):​c.1733A>T​(p.Asn578Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000435 in 919,477 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N578S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000044 (0 hom. 2 hem.)
• Consequence: LRCH2 NM_020871.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.98
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12824059).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

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.1733A>T	p.Asn578Ile	missense	Exon 15 of 21	NP_065922.3
	LRCH2	NM_001243963.2		c.1733A>T	p.Asn578Ile	missense	Exon 15 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.1733A>T	p.Asn578Ile	missense	Exon 15 of 21	ENSP00000325091.8	Q5VUJ6-1
	LRCH2	ENST00000538422.2	TSL:1	c.1733A>T	p.Asn578Ile	missense	Exon 15 of 20	ENSP00000439366.1	Q5VUJ6-2
	LRCH2	ENST00000857824.1		c.1712A>T	p.Asn571Ile	missense	Exon 15 of 21	ENSP00000527883.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000435 AC: 4 AN: 919477 Hom.: 0 Cov.: 15 AF XY: 0.00000763 AC XY: 2 AN XY: 261985

African (AFR) AF: 0.00 AC: 0 AN: 22024

American (AMR) AF: 0.00 AC: 0 AN: 25730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17034

East Asian (EAS) AF: 0.00 AC: 0 AN: 27182

South Asian (SAS) AF: 0.00 AC: 0 AN: 42610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37907

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3679

European-Non Finnish (NFE) AF: 0.00000568 AC: 4 AN: 704167

Other (OTH) AF: 0.00 AC: 0 AN: 39144

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	Benign	0.13
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.068
Sift	Benign	0.042	D
Sift4G	Benign	0.50	T
Polyphen		0.84	P
Vest4		0.33
MutPred		0.25		Gain of loop (P = 0.0312)
MVP		0.46
MPC		0.89
ClinPred		0.53	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.24
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

hg19: chrX-114364725;