21-36745009-G-C

Variant names:

• chr21-36745009-G-C
• NM_005069.6:c.1449G>C
• SIM2 p.Leu483Leu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP7

The NM_005069.6(SIM2):​c.1449G>C​(p.Leu483Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: SIM2 NM_005069.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22
• 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]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.258).
• BP7: Synonymous conserved (PhyloP=2.22 with no splicing effect.

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.1449G>C	p.Leu483Leu	synonymous	Exon 10 of 11	NP_005060.1	Q14190-1
	SIM2	NM_009586.5		c.1449G>C	p.Leu483Leu	synonymous	Exon 10 of 10	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.1449G>C	p.Leu483Leu	synonymous	Exon 10 of 11	ENSP00000290399.6	Q14190-1
	SIM2	ENST00000431229.1	TSL:1	c.1260G>C	p.Leu420Leu	synonymous	Exon 9 of 10	ENSP00000392003.1	H7BZX8
	SIM2	ENST00000481185.1	TSL:2	n.2062G>C		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		2.2

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

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

Other links and lift over

hg19: chr21-38117310;