rs79727992

Positions:

• chr21-36719771-G-A

Variant summary

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

The ENST00000290399.11(SIM2):​c.349-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 1,156,442 control chromosomes in the GnomAD database, including 978 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 0.032 (105 hom., cov: 32)
  • Exomes 𝑓: 0.038 (873 hom.)
• Consequence: SIM2 ENST00000290399.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.53

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=-0.86).
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIM2	NM_005069.6	c.349-50G>A		intron_variant		ENST00000290399.11	NP_005060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIM2	ENST00000290399.11	c.349-50G>A		intron_variant		1	NM_005069.6	ENSP00000290399	P1
SIM2	ENST00000431229.1	c.161-50G>A		intron_variant		1		ENSP00000392003
SIM2	ENST00000483178.2	c.58-50G>A		intron_variant		3		ENSP00000476273
SIM2	ENST00000481185.1	n.962-50G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0324 AC: 4924 AN: 152114 Hom.: 105 Cov.: 32

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0336

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.0559

Gnomad FIN AF: 0.0329

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0379

Gnomad OTH AF: 0.0465

GnomAD3 exomes AF: 0.0351 AC: 8689 AN: 247774 Hom.: 205 AF XY: 0.0367 AC XY: 4924 AN XY: 134084

Gnomad AFR exome AF: 0.0190

Gnomad AMR exome AF: 0.0237

Gnomad ASJ exome AF: 0.0440

Gnomad EAS exome AF: 0.00267

Gnomad SAS exome AF: 0.0553

Gnomad FIN exome AF: 0.0320

Gnomad NFE exome AF: 0.0403

Gnomad OTH exome AF: 0.0387

GnomAD4 exome AF: 0.0380 AC: 38204 AN: 1004210 Hom.: 873 Cov.: 13 AF XY: 0.0391 AC XY: 20266 AN XY: 518766

Gnomad4 AFR exome AF: 0.0182

Gnomad4 AMR exome AF: 0.0247

Gnomad4 ASJ exome AF: 0.0433

Gnomad4 EAS exome AF: 0.0237

Gnomad4 SAS exome AF: 0.0529

Gnomad4 FIN exome AF: 0.0318

Gnomad4 NFE exome AF: 0.0390

Gnomad4 OTH exome AF: 0.0374

GnomAD4 genome AF: 0.0324 AC: 4929 AN: 152232 Hom.: 105 Cov.: 32 AF XY: 0.0325 AC XY: 2422 AN XY: 74434

Gnomad4 AFR AF: 0.0212

Gnomad4 AMR AF: 0.0336

Gnomad4 ASJ AF: 0.0490

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.0553

Gnomad4 FIN AF: 0.0329

Gnomad4 NFE AF: 0.0379

Gnomad4 OTH AF: 0.0460

Alfa AF: 0.0352 Hom.: 21

Bravo AF: 0.0305

Asia WGS AF: 0.0330 AC: 115 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.032
DANN	Benign	0.65

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: rs79727992; hg19: chr21-38092072;