21-36741767-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005069.6(SIM2):​c.901C>T​(p.Arg301Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

SIM2
NM_005069.6 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.02
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SIM2NM_005069.6 linkuse as main transcriptc.901C>T p.Arg301Trp missense_variant 8/11 ENST00000290399.11 NP_005060.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SIM2ENST00000290399.11 linkuse as main transcriptc.901C>T p.Arg301Trp missense_variant 8/111 NM_005069.6 ENSP00000290399 P1Q14190-1
SIM2ENST00000431229.1 linkuse as main transcriptc.715C>T p.Arg239Trp missense_variant 7/101 ENSP00000392003
SIM2ENST00000481185.1 linkuse as main transcriptn.1514C>T non_coding_transcript_exon_variant 8/102

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000242
AC:
6
AN:
247858
Hom.:
0
AF XY:
0.0000223
AC XY:
3
AN XY:
134602
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000291
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0000658
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000893
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1460920
Hom.:
0
Cov.:
34
AF XY:
0.00000963
AC XY:
7
AN XY:
726746
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152180
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000850
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000247
AC:
3
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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 06, 2022The c.901C>T (p.R301W) alteration is located in exon 8 (coding exon 8) of the SIM2 gene. This alteration results from a C to T substitution at nucleotide position 901, causing the arginine (R) at amino acid position 301 to be replaced by a tryptophan (W). 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
0.10
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.45
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.77
D
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.95
D
M_CAP
Benign
0.0074
T
MetaRNN
Uncertain
0.58
D
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.3
L
MutationTaster
Benign
0.75
N;N
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-3.3
D
REVEL
Benign
0.16
Sift
Uncertain
0.013
D
Sift4G
Uncertain
0.019
D
Polyphen
0.92
P
Vest4
0.42
MutPred
0.52
Loss of loop (P = 0.0986);
MVP
0.58
MPC
0.83
ClinPred
0.73
D
GERP RS
4.3
Varity_R
0.24
gMVP
0.42

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.

Other links and lift over

dbSNP: rs772274383; hg19: chr21-38114068; COSMIC: COSV51769861; API