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GeneBe

9-124015447-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_004789.4(LHX2):c.649G>A(p.Val217Met) variant causes a missense change. The variant allele was found at a frequency of 0.000443 in 1,568,810 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00044 ( 8 hom. )

Consequence

LHX2
NM_004789.4 missense

Scores

2
7
9

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.09
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.010335803).
BP6
Variant 9-124015447-G-A is Benign according to our data. Variant chr9-124015447-G-A is described in ClinVar as [Benign]. Clinvar id is 3046005.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd at 65 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LHX2NM_004789.4 linkuse as main transcriptc.649G>A p.Val217Met missense_variant 3/5 ENST00000373615.9
LHX2XM_006717323.4 linkuse as main transcriptc.649G>A p.Val217Met missense_variant 3/6
LHX2XM_047424082.1 linkuse as main transcriptc.649G>A p.Val217Met missense_variant 3/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LHX2ENST00000373615.9 linkuse as main transcriptc.649G>A p.Val217Met missense_variant 3/51 NM_004789.4 P1
LHX2ENST00000446480.5 linkuse as main transcriptc.667G>A p.Val223Met missense_variant 3/52
LHX2ENST00000488674.2 linkuse as main transcriptc.52G>A p.Val18Met missense_variant 1/43

Frequencies

GnomAD3 genomes
AF:
0.000427
AC:
65
AN:
152266
Hom.:
0
Cov.:
32
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:
0.0121
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000962
AC:
185
AN:
192342
Hom.:
4
AF XY:
0.000986
AC XY:
103
AN XY:
104500
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000375
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0113
Gnomad SAS exome
AF:
0.000305
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000462
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000445
AC:
630
AN:
1416426
Hom.:
8
Cov.:
32
AF XY:
0.000474
AC XY:
332
AN XY:
700808
show subpopulations
Gnomad4 AFR exome
AF:
0.0000314
Gnomad4 AMR exome
AF:
0.0000267
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0150
Gnomad4 SAS exome
AF:
0.000275
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000110
Gnomad4 OTH exome
AF:
0.000258
GnomAD4 genome
AF:
0.000427
AC:
65
AN:
152384
Hom.:
0
Cov.:
32
AF XY:
0.000429
AC XY:
32
AN XY:
74514
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0121
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000507
Hom.:
1
Bravo
AF:
0.000446
ExAC
AF:
0.000830
AC:
99
Asia WGS
AF:
0.00375
AC:
13
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

LHX2-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 28, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.15
Cadd
Uncertain
24
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.44
T
Eigen
Uncertain
0.31
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.89
D
MetaRNN
Benign
0.010
T
MetaSVM
Uncertain
0.057
D
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
0.94
D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-0.77
N
REVEL
Uncertain
0.42
Sift
Benign
0.081
T
Sift4G
Benign
0.096
T
Polyphen
0.69
P
Vest4
0.57
MVP
0.78
MPC
2.1
ClinPred
0.10
T
GERP RS
4.5
Varity_R
0.14
gMVP
0.44

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.

Other links and lift over

dbSNP: rs189601606; hg19: chr9-126777726; API