rs2070650

Positions:

• chr21-36719738-A-C
• chr21-36719738-A-T

Variant summary

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

The NM_005069.6(SIM2):​c.349-83A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 787,072 control chromosomes in the GnomAD database, including 129,697 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 0.56 (23614 hom., cov: 31)
  • Exomes 𝑓: 0.58 (106083 hom.)
• Consequence: SIM2 NM_005069.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.48

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]

SIM2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIM2	NM_005069.6	c.349-83A>C		intron_variant		ENST00000290399.11	NP_005060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIM2	ENST00000290399.11	c.349-83A>C		intron_variant		1	NM_005069.6	ENSP00000290399.6
SIM2	ENST00000431229.1	c.160-83A>C		intron_variant		1		ENSP00000392003.1
SIM2	ENST00000483178.2	c.58-83A>C		intron_variant		3		ENSP00000476273.1
SIM2	ENST00000481185.1	n.962-83A>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.555 AC: 84274 AN: 151814 Hom.: 23576 Cov.: 31

Gnomad AFR AF: 0.498

Gnomad AMI AF: 0.640

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.527

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.583

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.546

GnomAD4 exome AF: 0.577 AC: 366512 AN: 635140 Hom.: 106083 AF XY: 0.577 AC XY: 196463 AN XY: 340334

Gnomad4 AFR exome AF: 0.502

Gnomad4 AMR exome AF: 0.624

Gnomad4 ASJ exome AF: 0.536

Gnomad4 EAS exome AF: 0.539

Gnomad4 SAS exome AF: 0.597

Gnomad4 FIN exome AF: 0.638

Gnomad4 NFE exome AF: 0.571

Gnomad4 OTH exome AF: 0.567

GnomAD4 genome AF: 0.555 AC: 84364 AN: 151932 Hom.: 23614 Cov.: 31 AF XY: 0.559 AC XY: 41532 AN XY: 74246

Gnomad4 AFR AF: 0.498

Gnomad4 AMR AF: 0.578

Gnomad4 ASJ AF: 0.527

Gnomad4 EAS AF: 0.531

Gnomad4 SAS AF: 0.582

Gnomad4 FIN AF: 0.644

Gnomad4 NFE AF: 0.572

Gnomad4 OTH AF: 0.551

Alfa AF: 0.557 Hom.: 29782

Bravo AF: 0.549

Asia WGS AF: 0.598 AC: 2083 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.17
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2070650; hg19: chr21-38092039; COSMIC: COSV51767765;