Variant chr9-124015235-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_004789.4(LHX2):c.437G>A(p.Cys146Tyr) 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 pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

LHX2
NM_004789.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 10.0

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 9-124015235-G-A is Pathogenic according to our data. Variant chr9-124015235-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3340939.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-124015235-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LHX2	NM_004789.4 linkuse as main transcript	c.437G>A	p.Cys146Tyr	missense_variant	3/5	ENST00000373615.9	NP_004780.3
LHX2	XM_006717323.4 linkuse as main transcript	c.437G>A	p.Cys146Tyr	missense_variant	3/6		XP_006717386.1
LHX2	XM_047424082.1 linkuse as main transcript	c.437G>A	p.Cys146Tyr	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.437G>A	p.Cys146Tyr	missense_variant	3/5	1	NM_004789.4	ENSP00000362717	P1
LHX2	ENST00000446480.5 linkuse as main transcript	c.455G>A	p.Cys152Tyr	missense_variant	3/5	2		ENSP00000394978
LHX2	ENST00000560961.2 linkuse as main transcript	c.314G>A	p.Cys105Tyr	missense_variant	3/3	3		ENSP00000453448

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 07, 2023

Published functional studies demonstrate a damaging effect with impaired transactivation (Schmid CM et al., 2023); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37057675) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

.;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

5.0

.;H

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.97

PROVEAN

Pathogenic

-11

D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

.;D

Vest4

0.94

MutPred

0.85

.;Gain of helix (P = 0.0854);

MVP

0.98

MPC

2.9

ClinPred

1.0

GERP RS

4.4

Varity_R

0.97

gMVP

0.99

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over