Genetic Variant NM_005069.6:c.172G>A (chr21-36699918-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005069.6(SIM2):c.172G>A(p.Glu58Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,445,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SIM2
NM_005069.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.67

Publications

0 publications found

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:

ENSG00000224269 (HGNC:):

ENSG00000224269 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31160927).

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.172G>A	p.Glu58Lys	missense	Exon 1 of 11	NP_005060.1	Q14190-1
	SIM2	NM_009586.5		c.172G>A	p.Glu58Lys	missense	Exon 1 of 10	NP_033664.2	Q14190-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIM2	ENST00000290399.11	TSL:1 MANE Select	c.172G>A	p.Glu58Lys	missense	Exon 1 of 11	ENSP00000290399.6	Q14190-1
SIM2	ENST00000460783.1	TSL:1	n.786G>A		non_coding_transcript_exon	Exon 1 of 2
SIM2	ENST00000481185.1	TSL:2	n.785G>A		non_coding_transcript_exon	Exon 1 of 10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1445716

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717766

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32930

American (AMR)

AF:

0.00

AC:

AN:

43380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25678

East Asian (EAS)

AF:

0.00

AC:

AN:

38812

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83462

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5600

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104666

Other (OTH)

AF:

0.0000167

AC:

AN:

59754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.010

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

PhyloP100

4.7

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.10

Sift

Benign

0.077

Sift4G

Benign

0.19

Polyphen

0.31

Vest4

0.27

MutPred

0.39

Gain of MoRF binding (P = 0.0055)

MVP

0.54

MPC

0.35

ClinPred

0.94

GERP RS

4.9

Varity_R

0.30

gMVP

0.49

Mutation Taster

=86/14

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over