rs2269188

Positions:

• chr21-36700056-G-C
• chr21-36700056-G-A

Variant summary

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

The NM_005069.6(SIM2):​c.175+135G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 912,362 control chromosomes in the GnomAD database, including 37,873 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 0.25 (5216 hom., cov: 33)
  • Exomes 𝑓: 0.29 (32657 hom.)
• Consequence: SIM2 NM_005069.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.318

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIM2	NM_005069.6	c.175+135G>C		intron_variant		ENST00000290399.11
SIM2	NM_009586.5	c.175+135G>C		intron_variant
SIM2	XM_017028442.3	c.175+135G>C		intron_variant
SIM2	XM_047440953.1	c.175+135G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIM2	ENST00000290399.11	c.175+135G>C		intron_variant		1	NM_005069.6	P1
	ENST00000430607.1	n.269-1213C>G		intron_variant, non_coding_transcript_variant		5
SIM2	ENST00000460783.1	n.789+135G>C		intron_variant, non_coding_transcript_variant		1
SIM2	ENST00000481185.1	n.788+135G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37910 AN: 151998 Hom.: 5206 Cov.: 33

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.403

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.517

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.252

GnomAD4 exome AF: 0.286 AC: 217335 AN: 760246 Hom.: 32657 AF XY: 0.286 AC XY: 111237 AN XY: 388722

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.251

Gnomad4 ASJ exome AF: 0.299

Gnomad4 EAS exome AF: 0.477

Gnomad4 SAS exome AF: 0.299

Gnomad4 FIN exome AF: 0.275

Gnomad4 NFE exome AF: 0.280

Gnomad4 OTH exome AF: 0.290

GnomAD4 genome AF: 0.249 AC: 37941 AN: 152116 Hom.: 5216 Cov.: 33 AF XY: 0.249 AC XY: 18509 AN XY: 74376

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.261

Gnomad4 ASJ AF: 0.312

Gnomad4 EAS AF: 0.517

Gnomad4 SAS AF: 0.298

Gnomad4 FIN AF: 0.269

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.259

Alfa AF: 0.253 Hom.: 662

Bravo AF: 0.244

Asia WGS AF: 0.415 AC: 1441 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.9
DANN	Benign	0.74

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: rs2269188; hg19: chr21-38072356;