NM_005069.6:c.349-83A>C

Variant names:

• chr21-36719738-A-C
• rs2070650
• NM_005069.6:c.349-83A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 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 -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 rank	MANE	Protein	UniProt
SIM2	NM_005069.6	c.349-83A>C		intron_variant	Intron 3 of 10	ENST00000290399.11	NP_005060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIM2	ENST00000290399.11	c.349-83A>C		intron_variant	Intron 3 of 10	1	NM_005069.6	ENSP00000290399.6
SIM2	ENST00000431229.1	c.160-83A>C		intron_variant	Intron 2 of 9	1		ENSP00000392003.1
SIM2	ENST00000483178.2	c.58-83A>C		intron_variant	Intron 1 of 1	3		ENSP00000476273.1
SIM2	ENST00000481185.1	n.962-83A>C		intron_variant	Intron 3 of 9	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

African (AFR) AF: 0.502 AC: 8834 AN: 17614

American (AMR) AF: 0.624 AC: 25489 AN: 40862

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 10543 AN: 19682

East Asian (EAS) AF: 0.539 AC: 19249 AN: 35718

South Asian (SAS) AF: 0.597 AC: 39712 AN: 66552

European-Finnish (FIN) AF: 0.638 AC: 32445 AN: 50884

Middle Eastern (MID) AF: 0.526 AC: 1322 AN: 2512

European-Non Finnish (NFE) AF: 0.571 AC: 210340 AN: 368532

Other (OTH) AF: 0.567 AC: 18578 AN: 32784

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

African (AFR) AF: 0.498 AC: 20642 AN: 41440

American (AMR) AF: 0.578 AC: 8829 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 1829 AN: 3468

East Asian (EAS) AF: 0.531 AC: 2732 AN: 5142

South Asian (SAS) AF: 0.582 AC: 2797 AN: 4806

European-Finnish (FIN) AF: 0.644 AC: 6792 AN: 10546

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.572 AC: 38852 AN: 67940

Other (OTH) AF: 0.551 AC: 1162 AN: 2108

Alfa AF: 0.556 Hom.: 38261

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
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2070650; hg19: chr21-38092039; COSMIC: COSV51767765;