Variant chr9-124015502-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004789.4(LHX2):c.704C>T(p.Ala235Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000613 in 1,467,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000061 ( 0 hom. )

Consequence

LHX2
NM_004789.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.64

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23059514).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LHX2	NM_004789.4 linkuse as main transcript	c.704C>T	p.Ala235Val	missense_variant	3/5	ENST00000373615.9	NP_004780.3
LHX2	XM_006717323.4 linkuse as main transcript	c.704C>T	p.Ala235Val	missense_variant	3/6		XP_006717386.1
LHX2	XM_047424082.1 linkuse as main transcript	c.704C>T	p.Ala235Val	missense_variant	3/6		XP_047280038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LHX2	ENST00000373615.9 linkuse as main transcript	c.704C>T	p.Ala235Val	missense_variant	3/5	1	NM_004789.4	ENSP00000362717	P1
LHX2	ENST00000446480.5 linkuse as main transcript	c.722C>T	p.Ala241Val	missense_variant	3/5	2		ENSP00000394978
LHX2	ENST00000488674.2 linkuse as main transcript	c.107C>T	p.Ala36Val	missense_variant	1/4	3		ENSP00000476200

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000608

AC:

AN:

1315430

Hom.:

Cov.:

AF XY:

0.00000156

AC XY:

AN XY:

639966

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000768

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2023

The c.704C>T (p.A235V) alteration is located in exon 3 (coding exon 3) of the LHX2 gene. This alteration results from a C to T substitution at nucleotide position 704, causing the alanine (A) at amino acid position 235 to be replaced by a valine (V). 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

0.13

BayesDel_addAF

Benign

-0.0072

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.82

M_CAP

Benign

0.054

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.3

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.61

REVEL

Uncertain

0.36

Sift

Benign

0.40

Sift4G

Benign

0.41

Polyphen

0.86

Vest4

0.25

MutPred

0.22

Gain of MoRF binding (P = 0.1015);

MVP

0.61

MPC

1.4

ClinPred

0.53

GERP RS

3.3

Varity_R

0.11

gMVP

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over