9-124015492-G-A

Position:

• chr9-124015492-G-A

Variant summary

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

The NM_004789.4(LHX2):​c.694G>A​(p.Gly232Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LHX2 NM_004789.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.73

Genes affected

LHX2 (HGNC:6594): (LIM homeobox 2) This gene encodes a protein belonging to a large protein family, members of which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein may function as a transcriptional regulator. The protein can recapitulate or rescue phenotypes in Drosophila caused by a related protein, suggesting conservation of function during evolution. [provided by RefSeq, Jul 2008]

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/exons	MANE	Protein	UniProt
LHX2	NM_004789.4	c.694G>A	p.Gly232Ser	missense_variant	3/5	ENST00000373615.9	NP_004780.3
LHX2	XM_006717323.4	c.694G>A	p.Gly232Ser	missense_variant	3/6		XP_006717386.1
LHX2	XM_047424082.1	c.694G>A	p.Gly232Ser	missense_variant	3/6		XP_047280038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHX2	ENST00000373615.9	c.694G>A	p.Gly232Ser	missense_variant	3/5	1	NM_004789.4	ENSP00000362717.4
LHX2	ENST00000446480.5	c.709G>A	p.Gly237Ser	missense_variant	3/5	2		ENSP00000394978.1
LHX2	ENST00000488674.2	c.94G>A	p.Gly32Ser	missense_variant	1/4	3		ENSP00000476200.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Sep 26, 2024

The c.694G>A (p.G232S) alteration is located in exon 3 (coding exon 3) of the LHX2 gene. This alteration results from a G to A substitution at nucleotide position 694, causing the glycine (G) at amino acid position 232 to be replaced by a serine (S). 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	0.19
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.047
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.9	L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.16	N
REVEL	Uncertain	0.41
Sift	Benign	0.23	T
Sift4G	Benign	0.81	T
Polyphen		0.26	B
Vest4		0.57
MutPred		0.31		Gain of glycosylation at G232 (P = 0.0196);
MVP		0.83
MPC		2.1
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.16
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs1859172466; hg19: chr9-126777771;