chr21-36745007-C-A

Variant names:

• chr21-36745007-C-A
• rs2073601
• NM_005069.6:c.1447C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005069.6(SIM2):​c.1447C>A​(p.Leu483Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,614,150 control chromosomes in the GnomAD database, including 90,506 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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 (5912 hom., cov: 34)
  • Exomes 𝑓: 0.33 (84594 hom.)
• Consequence: SIM2 NM_005069.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.535
• Publications: 37 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 (MetaRNN=0.0041163564).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005069.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM2	NM_005069.6	MANE Select	c.1447C>A	p.Leu483Met	missense	Exon 10 of 11	NP_005060.1	Q14190-1
	SIM2	NM_009586.5		c.1447C>A	p.Leu483Met	missense	Exon 10 of 10	NP_033664.2	Q14190-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM2	ENST00000290399.11	TSL:1 MANE Select	c.1447C>A	p.Leu483Met	missense	Exon 10 of 11	ENSP00000290399.6	Q14190-1
	SIM2	ENST00000431229.1	TSL:1	c.1258C>A	p.Leu420Met	missense	Exon 9 of 10	ENSP00000392003.1	H7BZX8
	SIM2	ENST00000481185.1	TSL:2	n.2060C>A		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38090 AN: 152176 Hom.: 5913 Cov.: 34

Gnomad AFR AF: 0.0886

Gnomad AMI AF: 0.554

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.0481

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.259

GnomAD2 exomes AF: 0.275 AC: 69136 AN: 251064 AF XY: 0.288

Gnomad AFR exome AF: 0.0847

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.355

Gnomad EAS exome AF: 0.0469

Gnomad FIN exome AF: 0.334

Gnomad NFE exome AF: 0.350

Gnomad OTH exome AF: 0.300

GnomAD4 exome AF: 0.331 AC: 483164 AN: 1461856 Hom.: 84594 Cov.: 74 AF XY: 0.331 AC XY: 240948 AN XY: 727230

African (AFR) AF: 0.0816 AC: 2731 AN: 33480

American (AMR) AF: 0.154 AC: 6871 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 9207 AN: 26134

East Asian (EAS) AF: 0.0387 AC: 1538 AN: 39700

South Asian (SAS) AF: 0.310 AC: 26745 AN: 86258

European-Finnish (FIN) AF: 0.332 AC: 17704 AN: 53400

Middle Eastern (MID) AF: 0.299 AC: 1724 AN: 5768

European-Non Finnish (NFE) AF: 0.358 AC: 398215 AN: 1112002

Other (OTH) AF: 0.305 AC: 18429 AN: 60394

GnomAD4 genome AF: 0.250 AC: 38086 AN: 152294 Hom.: 5912 Cov.: 34 AF XY: 0.247 AC XY: 18390 AN XY: 74464

African (AFR) AF: 0.0885 AC: 3680 AN: 41584

American (AMR) AF: 0.199 AC: 3043 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1170 AN: 3472

East Asian (EAS) AF: 0.0476 AC: 247 AN: 5184

South Asian (SAS) AF: 0.310 AC: 1495 AN: 4830

European-Finnish (FIN) AF: 0.321 AC: 3407 AN: 10602

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.352 AC: 23921 AN: 68010

Other (OTH) AF: 0.255 AC: 540 AN: 2114

Alfa AF: 0.312 Hom.: 30234

Bravo AF: 0.233

TwinsUK AF: 0.361 AC: 1337

ALSPAC AF: 0.376 AC: 1448

ESP6500AA AF: 0.0951 AC: 419

ESP6500EA AF: 0.356 AC: 3062

ExAC AF: 0.278 AC: 33718

Asia WGS AF: 0.149 AC: 516 AN: 3478

EpiCase AF: 0.348

EpiControl AF: 0.340

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.066
Eigen_PC	Benign	0.047
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.54
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.10
Sift	Benign	0.12	T
Sift4G	Benign	0.17	T
Polyphen		0.97	D
Vest4		0.20
MPC		0.97
ClinPred		0.021	T
GERP RS		3.5
Varity_R		0.16
gMVP		0.25
Mutation Taster		=96/4	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: rs2073601; hg19: chr21-38117308; COSMIC: COSV51771097;