Variant 9-124015381-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004789.4(LHX2):c.583G>C(p.Ala195Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,609,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000014 ( 0 hom. )

Consequence

LHX2
NM_004789.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21

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 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=0.17466778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LHX2	NM_004789.4 linkuse as main transcript	c.583G>C	p.Ala195Pro	missense_variant	3/5	ENST00000373615.9
LHX2	XM_006717323.4 linkuse as main transcript	c.583G>C	p.Ala195Pro	missense_variant	3/6
LHX2	XM_047424082.1 linkuse as main transcript	c.583G>C	p.Ala195Pro	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LHX2	ENST00000373615.9 linkuse as main transcript	c.583G>C	p.Ala195Pro	missense_variant	3/5	1	NM_004789.4	P1
LHX2	ENST00000446480.5 linkuse as main transcript	c.601G>C	p.Ala201Pro	missense_variant	3/5	2
LHX2	ENST00000488674.2 linkuse as main transcript			upstream_gene_variant		3
LHX2	ENST00000560961.2 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152250

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:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457298

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724540

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Feb 15, 2023

The c.583G>C (p.A195P) alteration is located in exon 3 (coding exon 3) of the LHX2 gene. This alteration results from a G to C substitution at nucleotide position 583, causing the alanine (A) at amino acid position 195 to be replaced by a proline (P). 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

0.11

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.26

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.0

MutationTaster

Benign

0.58

PrimateAI

Uncertain

0.70

PROVEAN

Benign

1.8

REVEL

Benign

0.15

Sift

Benign

0.34

Sift4G

Benign

0.32

Polyphen

0.0

Vest4

0.29

MutPred

0.44

Gain of glycosylation at A195 (P = 0.0078);

MVP

0.61

MPC

1.5

ClinPred

0.18

GERP RS

4.3

Varity_R

0.17

gMVP

0.50

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