rs16994404

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_005069.6(SIM2):​c.399C>T​(p.His133His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00797 in 1,613,212 control chromosomes in the GnomAD database, including 827 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 0.041 ( 422 hom., cov: 32)
Exomes 𝑓: 0.0046 ( 405 hom. )

Consequence

SIM2
NM_005069.6 synonymous

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.53

Publications

2 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]

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ACMG classification

Classification was made for transcript

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

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.4).
BP7
Synonymous conserved (PhyloP=-2.53 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SIM2NM_005069.6 linkc.399C>T p.His133His synonymous_variant Exon 4 of 11 ENST00000290399.11 NP_005060.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SIM2ENST00000290399.11 linkc.399C>T p.His133His synonymous_variant Exon 4 of 11 1 NM_005069.6 ENSP00000290399.6 Q14190-1
SIM2ENST00000431229.1 linkc.210C>T p.His70His synonymous_variant Exon 3 of 10 1 ENSP00000392003.1 H7BZX8
SIM2ENST00000483178.2 linkc.108C>T p.His36His synonymous_variant Exon 2 of 2 3 ENSP00000476273.1 V9GY04
SIM2ENST00000481185.1 linkn.1012C>T non_coding_transcript_exon_variant Exon 4 of 10 2

Frequencies

GnomAD3 genomes
AF:
0.0406
AC:
6171
AN:
151868
Hom.:
422
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.139
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0185
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000623
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0190
Gnomad NFE
AF:
0.000971
Gnomad OTH
AF:
0.0335
GnomAD2 exomes
AF:
0.0112
AC:
2815
AN:
251406
AF XY:
0.00835
show subpopulations
Gnomad AFR exome
AF:
0.147
Gnomad AMR exome
AF:
0.00804
Gnomad ASJ exome
AF:
0.000496
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000730
Gnomad OTH exome
AF:
0.00668
GnomAD4 exome
AF:
0.00458
AC:
6690
AN:
1461226
Hom.:
405
Cov.:
31
AF XY:
0.00401
AC XY:
2912
AN XY:
727002
show subpopulations
African (AFR)
AF:
0.148
AC:
4952
AN:
33422
American (AMR)
AF:
0.00919
AC:
411
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.000306
AC:
8
AN:
26124
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000580
AC:
50
AN:
86242
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53324
Middle Eastern (MID)
AF:
0.0113
AC:
65
AN:
5760
European-Non Finnish (NFE)
AF:
0.000573
AC:
637
AN:
1111562
Other (OTH)
AF:
0.00939
AC:
567
AN:
60370
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.447
Heterozygous variant carriers
0
291
583
874
1166
1457
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
162
324
486
648
810
<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
AF:
0.0406
AC:
6175
AN:
151986
Hom.:
422
Cov.:
32
AF XY:
0.0395
AC XY:
2937
AN XY:
74308
show subpopulations
African (AFR)
AF:
0.139
AC:
5747
AN:
41378
American (AMR)
AF:
0.0185
AC:
283
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.000576
AC:
2
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.000623
AC:
3
AN:
4814
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10558
Middle Eastern (MID)
AF:
0.0136
AC:
4
AN:
294
European-Non Finnish (NFE)
AF:
0.000971
AC:
66
AN:
67986
Other (OTH)
AF:
0.0332
AC:
70
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.493
Heterozygous variant carriers
0
255
510
764
1019
1274
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
62
124
186
248
310
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0216
Hom.:
189
Bravo
AF:
0.0477
Asia WGS
AF:
0.00664
AC:
24
AN:
3478
EpiCase
AF:
0.000545
EpiControl
AF:
0.000771

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.40
CADD
Benign
5.4
DANN
Benign
0.86
PhyloP100
-2.5
Mutation Taster
=98/2
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs16994404; hg19: chr21-38092172; API