9-124021154-G-C

Variant names:

• chr9-124021154-G-C
• rs1042486
• NM_004789.4:c.783G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP7 BA1

The NM_004789.4(LHX2):​c.783G>C​(p.Pro261Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 1,613,834 control chromosomes in the GnomAD database, including 160,691 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (12371 hom., cov: 32)
  • Exomes 𝑓: 0.45 (148320 hom.)
• Consequence: LHX2 NM_004789.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0450
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.199).
• BP7: Synonymous conserved (PhyloP=-0.045 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.478 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHX2	NM_004789.4	c.783G>C	p.Pro261Pro	synonymous_variant	Exon 4 of 5	ENST00000373615.9	NP_004780.3
LHX2	XM_006717323.4	c.783G>C	p.Pro261Pro	synonymous_variant	Exon 4 of 6		XP_006717386.1
LHX2	XM_047424082.1	c.783G>C	p.Pro261Pro	synonymous_variant	Exon 4 of 6		XP_047280038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHX2	ENST00000373615.9	c.783G>C	p.Pro261Pro	synonymous_variant	Exon 4 of 5	1	NM_004789.4	ENSP00000362717.4
LHX2	ENST00000446480.5	c.798G>C	p.Pro266Pro	synonymous_variant	Exon 4 of 5	2		ENSP00000394978.1
LHX2	ENST00000488674.2	c.183G>C	p.Pro61Pro	synonymous_variant	Exon 2 of 4	3		ENSP00000476200.1

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59352 AN: 151946 Hom.: 12364 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.494

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.385

GnomAD2 exomes AF: 0.433 AC: 108766 AN: 251210 AF XY: 0.426

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.578

Gnomad ASJ exome AF: 0.342

Gnomad EAS exome AF: 0.426

Gnomad FIN exome AF: 0.479

Gnomad NFE exome AF: 0.451

Gnomad OTH exome AF: 0.418

GnomAD4 exome AF: 0.445 AC: 650880 AN: 1461770 Hom.: 148320 Cov.: 60 AF XY: 0.440 AC XY: 320187 AN XY: 727190

African (AFR) AF: 0.217 AC: 7268 AN: 33476

American (AMR) AF: 0.570 AC: 25480 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 9022 AN: 26136

East Asian (EAS) AF: 0.461 AC: 18305 AN: 39690

South Asian (SAS) AF: 0.318 AC: 27465 AN: 86250

European-Finnish (FIN) AF: 0.482 AC: 25727 AN: 53378

Middle Eastern (MID) AF: 0.278 AC: 1604 AN: 5768

European-Non Finnish (NFE) AF: 0.459 AC: 510889 AN: 1111972

Other (OTH) AF: 0.416 AC: 25120 AN: 60394

GnomAD4 genome AF: 0.391 AC: 59392 AN: 152064 Hom.: 12371 Cov.: 32 AF XY: 0.389 AC XY: 28931 AN XY: 74336

African (AFR) AF: 0.233 AC: 9646 AN: 41480

American (AMR) AF: 0.487 AC: 7453 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1148 AN: 3470

East Asian (EAS) AF: 0.426 AC: 2204 AN: 5172

South Asian (SAS) AF: 0.333 AC: 1604 AN: 4816

European-Finnish (FIN) AF: 0.485 AC: 5122 AN: 10550

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.454 AC: 30870 AN: 67962

Other (OTH) AF: 0.384 AC: 811 AN: 2114

Alfa AF: 0.410 Hom.: 2418

Bravo AF: 0.386

Asia WGS AF: 0.373 AC: 1294 AN: 3478

EpiCase AF: 0.435

EpiControl AF: 0.427

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.68
DANN	Benign	0.77
PhyloP100		-0.045
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1042486; hg19: chr9-126783433; COSMIC: COSV65317799;