rs16994404

chr21-36719871-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_005069.6(SIM2):c.399C>T(p.His133=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00797 in 1,613,212 control chromosomes in the GnomAD database, including 827 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 0.041 (422 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (405 hom.)
• Consequence: SIM2 NM_005069.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.53

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP7: Synonymous conserved (PhyloP=-2.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIM2	NM_005069.6	c.399C>T	p.His133=	synonymous_variant	4/11	ENST00000290399.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIM2	ENST00000290399.11	c.399C>T	p.His133=	synonymous_variant	4/11	1	NM_005069.6	P1
SIM2	ENST00000431229.1	c.213C>T	p.His71=	synonymous_variant	3/10	1
SIM2	ENST00000483178.2	c.108C>T	p.His36=	synonymous_variant	2/2	3
SIM2	ENST00000481185.1	n.1012C>T		non_coding_transcript_exon_variant	4/10	2

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6171 AN: 151868 Hom.: 422 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.0335

GnomAD3 exomes AF: 0.0112 AC: 2815 AN: 251406 Hom.: 195 AF XY: 0.00835 AC XY: 1135 AN XY: 135890

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.00804

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000730

Gnomad OTH exome AF: 0.00668

GnomAD4 exome AF: 0.00458 AC: 6690 AN: 1461226 Hom.: 405 Cov.: 31 AF XY: 0.00401 AC XY: 2912 AN XY: 727002

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.00919

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000573

Gnomad4 OTH exome AF: 0.00939

GnomAD4 genome AF: 0.0406 AC: 6175 AN: 151986 Hom.: 422 Cov.: 32 AF XY: 0.0395 AC XY: 2937 AN XY: 74308

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.0185

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000971

Gnomad4 OTH AF: 0.0332

Alfa AF: 0.0239 Hom.: 136

Bravo AF: 0.0477

Asia WGS AF: 0.00664 AC: 24 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000771

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	5.4
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs16994404; hg19: chr21-38092172;