Variant chr21-36745007-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.25 ( 5912 hom., cov: 34)

Exomes 𝑓: 0.33 ( 84594 hom. )

Consequence

SIM2
NM_005069.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.535

Variant links:

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]

SIM2 links:

SIM2 (HGNC:):

SIM2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SIM2	NM_005069.6 linkuse as main transcript	c.1447C>A	p.Leu483Met	missense_variant	10/11	ENST00000290399.11	NP_005060.1
SIM2	NM_009586.5 linkuse as main transcript	c.1447C>A	p.Leu483Met	missense_variant	10/10		NP_033664.2
SIM2	XM_011529694.2 linkuse as main transcript	c.1144C>A	p.Leu382Met	missense_variant	9/10		XP_011527996.1
SIM2	XM_047440952.1 linkuse as main transcript	c.1144C>A	p.Leu382Met	missense_variant	9/10		XP_047296908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SIM2	ENST00000290399.11 linkuse as main transcript	c.1447C>A	p.Leu483Met	missense_variant	10/11	1	NM_005069.6	ENSP00000290399.6	Q14190-1
SIM2	ENST00000431229.1 linkuse as main transcript	c.1258C>A	p.Leu420Met	missense_variant	9/10	1		ENSP00000392003.1	H7BZX8
SIM2	ENST00000481185.1 linkuse as main transcript	n.2060C>A		non_coding_transcript_exon_variant	10/10	2

Frequencies

GnomAD3 genomes

AF:

0.250

AC:

38090

AN:

152176

Hom.:

5913

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.275

AC:

69136

AN:

251064

Hom.:

11157

AF XY:

0.288

AC XY:

39116

AN XY:

135718

show subpopulations

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 SAS exome

AF:

0.308

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.:

AF XY:

0.331

AC XY:

240948

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0816

Gnomad4 AMR exome

AF:

0.154

Gnomad4 ASJ exome

AF:

0.352

Gnomad4 EAS exome

AF:

0.0387

Gnomad4 SAS exome

AF:

0.310

Gnomad4 FIN exome

AF:

0.332

Gnomad4 NFE exome

AF:

0.358

Gnomad4 OTH exome

AF:

0.305

GnomAD4 genome

AF:

0.250

AC:

38086

AN:

152294

Hom.:

5912

Cov.:

AF XY:

0.247

AC XY:

18390

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0885

Gnomad4 AMR

AF:

0.199

Gnomad4 ASJ

AF:

0.337

Gnomad4 EAS

AF:

0.0476

Gnomad4 SAS

AF:

0.310

Gnomad4 FIN

AF:

0.321

Gnomad4 NFE

AF:

0.352

Gnomad4 OTH

AF:

0.255

Alfa

AF:

0.316

Hom.:

15549

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Benign

0.066

Eigen_PC

Benign

0.047

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0041

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.52

REVEL

Benign

0.10

Sift

Benign

0.12

Sift4G

Benign

0.17

Polyphen

0.97

Vest4

0.20

MPC

0.97

ClinPred

0.021

GERP RS

3.5

Varity_R

0.16

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over