rs2073416

Variant names:

• chr21-36744739-G-A
• rs2073416
• NM_005069.6:c.1179G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-36744739-G-A
• chr21-36744739-G-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_005069.6(SIM2):​c.1179G>A​(p.Ser393Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,601,752 control chromosomes in the GnomAD database, including 39,180 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 (5348 hom., cov: 33)
  • Exomes 𝑓: 0.21 (33832 hom.)
• Consequence: SIM2 NM_005069.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.243
• Publications: 17 publications found

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

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.06).
• BP7: Synonymous conserved (PhyloP=-0.243 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIM2	NM_005069.6	c.1179G>A	p.Ser393Ser	synonymous_variant	Exon 10 of 11	ENST00000290399.11	NP_005060.1
SIM2	NM_009586.5	c.1179G>A	p.Ser393Ser	synonymous_variant	Exon 10 of 10		NP_033664.2
SIM2	XM_011529694.2	c.876G>A	p.Ser292Ser	synonymous_variant	Exon 9 of 10		XP_011527996.1
SIM2	XM_047440952.1	c.876G>A	p.Ser292Ser	synonymous_variant	Exon 9 of 10		XP_047296908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIM2	ENST00000290399.11	c.1179G>A	p.Ser393Ser	synonymous_variant	Exon 10 of 11	1	NM_005069.6	ENSP00000290399.6
SIM2	ENST00000431229.1	c.990G>A	p.Ser330Ser	synonymous_variant	Exon 9 of 10	1		ENSP00000392003.1
SIM2	ENST00000481185.1	n.1792G>A		non_coding_transcript_exon_variant	Exon 10 of 10	2

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38726 AN: 152012 Hom.: 5343 Cov.: 33

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.250

GnomAD2 exomes AF: 0.220 AC: 50494 AN: 229584 AF XY: 0.221

Gnomad AFR exome AF: 0.367

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.293

Gnomad EAS exome AF: 0.229

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.241

GnomAD4 exome AF: 0.211 AC: 306413 AN: 1449622 Hom.: 33832 Cov.: 34 AF XY: 0.213 AC XY: 153278 AN XY: 719860

African (AFR) AF: 0.379 AC: 12615 AN: 33252

American (AMR) AF: 0.167 AC: 7123 AN: 42728

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 7660 AN: 25800

East Asian (EAS) AF: 0.282 AC: 11091 AN: 39284

South Asian (SAS) AF: 0.260 AC: 21967 AN: 84344

European-Finnish (FIN) AF: 0.182 AC: 9554 AN: 52588

Middle Eastern (MID) AF: 0.325 AC: 1869 AN: 5756

European-Non Finnish (NFE) AF: 0.200 AC: 220711 AN: 1105838

Other (OTH) AF: 0.230 AC: 13823 AN: 60032

GnomAD4 genome AF: 0.255 AC: 38751 AN: 152130 Hom.: 5348 Cov.: 33 AF XY: 0.254 AC XY: 18878 AN XY: 74366

African (AFR) AF: 0.364 AC: 15108 AN: 41504

American (AMR) AF: 0.214 AC: 3269 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1036 AN: 3466

East Asian (EAS) AF: 0.231 AC: 1190 AN: 5156

South Asian (SAS) AF: 0.270 AC: 1300 AN: 4818

European-Finnish (FIN) AF: 0.184 AC: 1948 AN: 10582

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.208 AC: 14147 AN: 67986

Other (OTH) AF: 0.248 AC: 524 AN: 2114

Alfa AF: 0.225 Hom.: 11969

Bravo AF: 0.260

Asia WGS AF: 0.263 AC: 913 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.4
DANN	Benign	0.87
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2073416; hg19: chr21-38117040; COSMIC: COSV51769118;