rs13050963

Positions:

• chr21-36719342-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005069.6(SIM2):​c.349-479C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0716 in 152,342 control chromosomes in the GnomAD database, including 517 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 0.072 (517 hom., cov: 34)
• Consequence: SIM2 NM_005069.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.86

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIM2	NM_005069.6	c.349-479C>T		intron_variant		ENST00000290399.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIM2	ENST00000290399.11	c.349-479C>T		intron_variant		1	NM_005069.6	P1
SIM2	ENST00000431229.1	c.161-479C>T		intron_variant		1
SIM2	ENST00000483178.2	c.58-479C>T		intron_variant		3
SIM2	ENST00000481185.1	n.962-479C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10915 AN: 152224 Hom.: 517 Cov.: 34

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.0757

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0694

Gnomad FIN AF: 0.0685

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.0703

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

GnomAD4 genome AF: 0.0716 AC: 10912 AN: 152342 Hom.: 517 Cov.: 34 AF XY: 0.0700 AC XY: 5215 AN XY: 74486

Gnomad4 AFR AF: 0.0201

Gnomad4 AMR AF: 0.0756

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0698

Gnomad4 FIN AF: 0.0685

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.0701

Alfa AF: 0.0944 Hom.: 358

Bravo AF: 0.0708

Asia WGS AF: 0.0350 AC: 120 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.19
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs13050963; hg19: chr21-38091643;