chrX-115165647-C-A

Variant names:

• chrX-115165647-C-A
• rs2072553218
• NM_020871.4:c.1207G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_020871.4(LRCH2):​c.1207G>T​(p.Val403Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000387 in 1,033,543 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000039 (0 hom. 2 hem.)
• Consequence: LRCH2 NM_020871.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043035448).
• 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.1207G>T	p.Val403Leu	missense	Exon 9 of 21	NP_065922.3
	LRCH2	NM_001243963.2		c.1207G>T	p.Val403Leu	missense	Exon 9 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.1207G>T	p.Val403Leu	missense	Exon 9 of 21	ENSP00000325091.8	Q5VUJ6-1
	LRCH2	ENST00000538422.2	TSL:1	c.1207G>T	p.Val403Leu	missense	Exon 9 of 20	ENSP00000439366.1	Q5VUJ6-2
	LRCH2	ENST00000857824.1		c.1186G>T	p.Val396Leu	missense	Exon 9 of 21	ENSP00000527883.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000387 AC: 4 AN: 1033543 Hom.: 0 Cov.: 25 AF XY: 0.00000619 AC XY: 2 AN XY: 323031

African (AFR) AF: 0.00 AC: 0 AN: 24551

American (AMR) AF: 0.00 AC: 0 AN: 28289

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18321

East Asian (EAS) AF: 0.00 AC: 0 AN: 27513

South Asian (SAS) AF: 0.0000207 AC: 1 AN: 48346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3824

European-Non Finnish (NFE) AF: 0.00000125 AC: 1 AN: 801043

Other (OTH) AF: 0.0000458 AC: 2 AN: 43698

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.84
DEOGEN2	Benign	0.052	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-0.55	N
PhyloP100		2.4
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.036
Sift	Benign	0.74	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.086
MutPred		0.22		Loss of disorder (P = 0.1184)
MVP		0.27
MPC		0.43
ClinPred		0.28	T
GERP RS		4.3
Varity_R		0.068
gMVP		0.072
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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

dbSNP: rs2072553218; hg19: chrX-114400210;