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GeneBe

21-36723063-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005069.6(SIM2):c.476C>T(p.Ser159Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SIM2
NM_005069.6 missense

Scores

5
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.42
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 made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SIM2NM_005069.6 linkuse as main transcriptc.476C>T p.Ser159Leu missense_variant 5/11 ENST00000290399.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SIM2ENST00000290399.11 linkuse as main transcriptc.476C>T p.Ser159Leu missense_variant 5/111 NM_005069.6 P1Q14190-1
SIM2ENST00000431229.1 linkuse as main transcriptc.290C>T p.Ser97Leu missense_variant 4/101
SIM2ENST00000481185.1 linkuse as main transcriptn.1089C>T non_coding_transcript_exon_variant 5/102

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461820
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 06, 2022The c.476C>T (p.S159L) alteration is located in exon 5 (coding exon 5) of the SIM2 gene. This alteration results from a C to T substitution at nucleotide position 476, causing the serine (S) at amino acid position 159 to be replaced by a leucine (L). 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
0.33
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
Cadd
Pathogenic
28
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.77
D
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Benign
0.059
D
MetaRNN
Pathogenic
0.88
D
MetaSVM
Benign
-0.31
T
MutationAssessor
Benign
1.9
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-4.4
D
REVEL
Pathogenic
0.72
Sift
Uncertain
0.0080
D
Sift4G
Benign
0.080
T
Polyphen
0.87
P
Vest4
0.96
MutPred
0.56
Gain of sheet (P = 0.0477);
MVP
0.85
MPC
0.90
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.51
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs2059329241; hg19: chr21-38095364; API