9-124032503-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004789.4(LHX2):c.1017G>C(p.Ala339=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000961 in 1,613,136 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (1 hom.)
• Consequence: LHX2 NM_004789.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.93

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 9-124032503-G-C is Benign according to our data. Variant chr9-124032503-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2659491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.93 with no splicing effect.
• BS2: High AC in GnomAd at 193 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHX2	NM_004789.4	c.1017G>C	p.Ala339=	synonymous_variant	5/5	ENST00000373615.9
LHX2	XM_006717323.4	c.*121G>C		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHX2	ENST00000373615.9	c.1017G>C	p.Ala339=	synonymous_variant	5/5	1	NM_004789.4	P1
	ENST00000429482.1	n.22C>G		non_coding_transcript_exon_variant	1/3	2
LHX2	ENST00000446480.5	c.1035G>C	p.Ala345=	synonymous_variant	5/5	2
LHX2	ENST00000488674.2	c.*121G>C		3_prime_UTR_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00500

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00133 AC: 332 AN: 249536 Hom.: 0 AF XY: 0.00115 AC XY: 155 AN XY: 135088

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00473

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.000930 AC: 1358 AN: 1460880 Hom.: 1 Cov.: 32 AF XY: 0.000890 AC XY: 647 AN XY: 726804

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00584

Gnomad4 NFE exome AF: 0.000856

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74434

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00500

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00126 Hom.: 0

Bravo AF: 0.000793

EpiCase AF: 0.000763

EpiControl AF: 0.000533

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LHX2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2022

LHX2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.40
Dann	Benign	0.75

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

Other links and lift over

dbSNP: rs138022431; hg19: chr9-126794782;