9-124015279-A-G

Position:

• chr9-124015279-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004789.4(LHX2):​c.481A>G​(p.Ser161Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LHX2 NM_004789.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18383193).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHX2	NM_004789.4	c.481A>G	p.Ser161Gly	missense_variant	3/5	ENST00000373615.9	NP_004780.3
LHX2	XM_006717323.4	c.481A>G	p.Ser161Gly	missense_variant	3/6		XP_006717386.1
LHX2	XM_047424082.1	c.481A>G	p.Ser161Gly	missense_variant	3/6		XP_047280038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHX2	ENST00000373615.9	c.481A>G	p.Ser161Gly	missense_variant	3/5	1	NM_004789.4	ENSP00000362717	P1
LHX2	ENST00000446480.5	c.499A>G	p.Ser167Gly	missense_variant	3/5	2		ENSP00000394978
LHX2	ENST00000560961.2	c.358A>G	p.Ser120Gly	missense_variant	3/3	3		ENSP00000453448

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Mar 25, 2024

The c.481A>G (p.S161G) alteration is located in exon 3 (coding exon 3) of the LHX2 gene. This alteration results from a A to G substitution at nucleotide position 481, causing the serine (S) at amino acid position 161 to be replaced by a glycine (G). 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	0.081
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.35	.;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.10
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-1.5	.;N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.46	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.68	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0060	.;B
Vest4		0.39
MutPred		0.44		.;Loss of relative solvent accessibility (P = 0.0306);
MVP		0.57
MPC		1.2
ClinPred		0.89	D
GERP RS		5.2
Varity_R		0.25
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-126777558;