21-36699918-GAA-CAG

Variant names:

• chr21-36699918-GAA-CAG
• NM_005069.6:c.172_174delGAAinsCAG
• SIM2 p.Glu58Gln

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005069.6(SIM2):​c.172_174delGAAinsCAG​(p.Glu58Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E58K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIM2 NM_005069.6 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.27
• Publications: 0 publications found

Genes affected

SIM2 (HGNC:10883): (SIM bHLH transcription factor 2) This gene represents a homolog of the Drosophila single-minded (sim) gene, which encodes a transcription factor that is a master regulator of neurogenesis. The encoded protein is ubiquitinated by RING-IBR-RING-type E3 ubiquitin ligases, including the parkin RBR E3 ubiquitin protein ligase. This gene maps within the so-called Down syndrome chromosomal region, and is thus thought to contribute to some specific Down syndrome phenotypes. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2014]

ENSG00000224269 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005069.6. 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
	SIM2	NM_005069.6	MANE Select	c.172_174delGAAinsCAG	p.Glu58Gln	missense splice_region	N/A	NP_005060.1	Q14190-1
	SIM2	NM_009586.5		c.172_174delGAAinsCAG	p.Glu58Gln	missense splice_region	N/A	NP_033664.2	Q14190-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM2	ENST00000290399.11	TSL:1 MANE Select	c.172_174delGAAinsCAG	p.Glu58Gln	missense splice_region	N/A	ENSP00000290399.6	Q14190-1
	SIM2	ENST00000460783.1	TSL:1	n.786_788delGAAinsCAG		splice_region non_coding_transcript_exon	Exon 1 of 2
	SIM2	ENST00000481185.1	TSL:2	n.785_787delGAAinsCAG		splice_region non_coding_transcript_exon	Exon 1 of 10

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr21-38072218;