9-124014131-C-G

Variant names:

• chr9-124014131-C-G
• rs144291200
• NM_004789.4:c.291C>G

Variant summary

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

The NM_004789.4(LHX2):​c.291C>G​(p.Asp97Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,170 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D97D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LHX2 NM_004789.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0410
• Publications: 0 publications found

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]

LHX2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics

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_004789.4. 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
	LHX2	NM_004789.4	MANE Select	c.291C>G	p.Asp97Glu	missense	Exon 2 of 5	NP_004780.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX2	ENST00000373615.9	TSL:1 MANE Select	c.291C>G	p.Asp97Glu	missense	Exon 2 of 5	ENSP00000362717.4	P50458
	LHX2	ENST00000446480.5	TSL:2	c.282C>G	p.Asp94Glu	missense	Exon 2 of 5	ENSP00000394978.1	H7C0H1
	LHX2	ENST00000560961.2	TSL:3	c.168C>G	p.Asp56Glu	missense	Exon 2 of 3	ENSP00000453448.3	H0YM35

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461170 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726906

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.041
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.70
Sift	Benign	0.087	T
Sift4G	Benign	0.25	T
Polyphen		0.72	P
Vest4		0.54
MutPred		0.49		Loss of sheet (P = 0.0457)
MVP		0.94
MPC		1.4
ClinPred		0.95	D
GERP RS		-1.3
Varity_R		0.19
gMVP		0.88
Mutation Taster		=31/69	disease causing

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

dbSNP: rs144291200; hg19: chr9-126776410;