9-124014131-C-T

Variant names:

• chr9-124014131-C-T
• rs144291200
• NM_004789.4:c.291C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6 BP7 BS2

The NM_004789.4(LHX2):​c.291C>T​(p.Asp97Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,613,466 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (11 hom.)
• Consequence: LHX2 NM_004789.4 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0410
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 9-124014131-C-T is Benign according to our data. Variant chr9-124014131-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3056509.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.041 with no splicing effect.
• BS2: High AC in GnomAd4 at 413 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004789.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX2	NM_004789.4	MANE Select	c.291C>T	p.Asp97Asp	synonymous	Exon 2 of 5	NP_004780.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX2	ENST00000373615.9	TSL:1 MANE Select	c.291C>T	p.Asp97Asp	synonymous	Exon 2 of 5	ENSP00000362717.4	P50458
	LHX2	ENST00000446480.5	TSL:2	c.282C>T	p.Asp94Asp	synonymous	Exon 2 of 5	ENSP00000394978.1	H7C0H1
	LHX2	ENST00000560961.2	TSL:3	c.168C>T	p.Asp56Asp	synonymous	Exon 2 of 3	ENSP00000453448.3	H0YM35

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 413 AN: 152184 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00362

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00252 AC: 630 AN: 250462 AF XY: 0.00239

Gnomad AFR exome AF: 0.000865

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00381 AC: 5565 AN: 1461164 Hom.: 11 Cov.: 33 AF XY: 0.00362 AC XY: 2635 AN XY: 726902

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.00324 AC: 145 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86256

European-Finnish (FIN) AF: 0.00114 AC: 60 AN: 52722

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00458 AC: 5090 AN: 1111992

Other (OTH) AF: 0.00358 AC: 216 AN: 60388

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152302 Hom.: 1 Cov.: 33 AF XY: 0.00274 AC XY: 204 AN XY: 74482

African (AFR) AF: 0.000697 AC: 29 AN: 41580

American (AMR) AF: 0.00706 AC: 108 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00362 AC: 246 AN: 68014

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00340 Hom.: 0

Bravo AF: 0.00292

EpiCase AF: 0.00431

EpiControl AF: 0.00433

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	LHX2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	2.2
DANN	Benign	0.83
PhyloP100		0.041
Mutation Taster		=100/0	polymorphism

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: rs144291200; hg19: chr9-126776410;