chr10-117543426-G-GGCC

Variant names:

• chr10-117543426-G-GGCC
• rs756693906
• NM_004098.4:c.176_178dupCCG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_004098.4(EMX2):​c.176_178dupCCG​(p.Ala59dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000538 in 1,597,602 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: EMX2 NM_004098.4 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.70
• Publications: 0 publications found

Genes affected

EMX2 (HGNC:3341): (empty spiracles homeobox 2) This gene encodes a homeobox-containing transcription factor that is the homolog to the 'empty spiracles' gene in Drosophila. Research on this gene in humans has focused on its expression in three tissues: dorsal telencephalon, olfactory neuroepithelium, and urogenetial system. It is expressed in the dorsal telencephalon during development in a low rostral-lateral to high caudal-medial gradient and is proposed to pattern the neocortex into defined functional areas. It is also expressed in embryonic and adult olfactory neuroepithelia where it complexes with eukaryotic translation initiation factor 4E (eIF4E) and possibly regulates mRNA transport or translation. In the developing urogenital system, it is expressed in epithelial tissues and is negatively regulated by HOXA10. Alternative splicing results in multiple transcript variants encoding distinct proteins.[provided by RefSeq, Sep 2009]

EMX2OS (HGNC:18511): (EMX2 opposite strand/antisense RNA)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004098.4
• BP6: Variant 10-117543426-G-GGCC is Benign according to our data. Variant chr10-117543426-G-GGCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290406.
• BS2: High AC in GnomAd4 at 6 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004098.4. 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
	EMX2	NM_004098.4	MANE Select	c.176_178dupCCG	p.Ala59dup	disruptive_inframe_insertion	Exon 1 of 3	NP_004089.1	Q04743-1
	EMX2	NM_001165924.2		c.176_178dupCCG	p.Ala59dup	disruptive_inframe_insertion	Exon 1 of 2	NP_001159396.1	Q04743-2
	EMX2OS	NR_002791.2		n.574+877_574+879dupGGC		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMX2	ENST00000553456.5	TSL:1 MANE Select	c.176_178dupCCG	p.Ala59dup	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000450962.3	Q04743-1
	EMX2OS	ENST00000551288.5	TSL:1	n.574+877_574+879dupGGC		intron	N/A
	EMX2	ENST00000442245.5	TSL:2	c.176_178dupCCG	p.Ala59dup	disruptive_inframe_insertion	Exon 1 of 2	ENSP00000474874.1	Q04743-2

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151830 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000577 AC: 12 AN: 208116 AF XY: 0.0000524

Gnomad AFR exome AF: 0.0000918

Gnomad AMR exome AF: 0.0000631

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000642

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000112

Gnomad OTH exome AF: 0.000382

GnomAD4 exome AF: 0.0000553 AC: 80 AN: 1445772 Hom.: 0 Cov.: 32 AF XY: 0.0000515 AC XY: 37 AN XY: 717916

African (AFR) AF: 0.000181 AC: 6 AN: 33102

American (AMR) AF: 0.0000464 AC: 2 AN: 43100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25774

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38656

South Asian (SAS) AF: 0.000154 AC: 13 AN: 84482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50254

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.0000480 AC: 53 AN: 1105016

Other (OTH) AF: 0.0000671 AC: 4 AN: 59638

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151830 Hom.: 0 Cov.: 29 AF XY: 0.0000539 AC XY: 4 AN XY: 74154

African (AFR) AF: 0.0000242 AC: 1 AN: 41300

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000729 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7
Mutation Taster		=72/28	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs756693906; hg19: chr10-119302937; COSMIC: COSV71294659; COSMIC: COSV71294659;