21-36726260-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005069.6(SIM2):​c.685A>G​(p.Ser229Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,613,668 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: š‘“ 0.000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.000022 ( 0 hom. )

Consequence

SIM2
NM_005069.6 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.74
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3344043).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SIM2NM_005069.6 linkc.685A>G p.Ser229Gly missense_variant Exon 6 of 11 ENST00000290399.11 NP_005060.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SIM2ENST00000290399.11 linkc.685A>G p.Ser229Gly missense_variant Exon 6 of 11 1 NM_005069.6 ENSP00000290399.6 Q14190-1
SIM2ENST00000431229.1 linkc.496A>G p.Ser166Gly missense_variant Exon 5 of 10 1 ENSP00000392003.1 H7BZX8
SIM2ENST00000481185.1 linkn.1298A>G non_coding_transcript_exon_variant Exon 6 of 10 2

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152194
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251186
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135770
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000219
AC:
32
AN:
1461474
Hom.:
0
Cov.:
31
AF XY:
0.0000220
AC XY:
16
AN XY:
727030
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000279
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152194
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000774
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 07, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.685A>G (p.S229G) alteration is located in exon 6 (coding exon 6) of the SIM2 gene. This alteration results from a A to G substitution at nucleotide position 685, causing the serine (S) at amino acid position 229 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.062
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.71
D
Eigen
Benign
0.16
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.33
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
M
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-3.6
D
REVEL
Benign
0.17
Sift
Benign
0.049
D
Sift4G
Benign
0.12
T
Polyphen
0.15
B
Vest4
0.46
MutPred
0.48
Gain of catalytic residue at S229 (P = 0.045);
MVP
0.47
MPC
0.28
ClinPred
0.29
T
GERP RS
4.3
Varity_R
0.50
gMVP
0.68

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs769465266; hg19: chr21-38098561; API