21-36699918-G-A

Position:

• chr21-36699918-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SIM2 NM_005069.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

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 (HGNC:):

ACMG classification

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=0.31160927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIM2	NM_005069.6	c.172G>A	p.Glu58Lys	missense_variant	1/11	ENST00000290399.11	NP_005060.1
SIM2	NM_009586.5	c.172G>A	p.Glu58Lys	missense_variant	1/10		NP_033664.2
SIM2	XM_017028442.3	c.172G>A	p.Glu58Lys	missense_variant	1/9		XP_016883931.1
SIM2	XM_047440953.1	c.172G>A	p.Glu58Lys	missense_variant	1/8		XP_047296909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIM2	ENST00000290399.11	c.172G>A	p.Glu58Lys	missense_variant	1/11	1	NM_005069.6	ENSP00000290399.6
SIM2	ENST00000460783.1	n.786G>A		non_coding_transcript_exon_variant	1/2	1
SIM2	ENST00000481185.1	n.785G>A		non_coding_transcript_exon_variant	1/10	2
ENSG00000224269	ENST00000430607.1	n.269-1075C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445716 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 717766

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: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2024

The c.172G>A (p.E58K) alteration is located in exon 1 (coding exon 1) of the SIM2 gene. This alteration results from a G to A substitution at nucleotide position 172, causing the glutamic acid (E) at amino acid position 58 to be replaced by a lysine (K). 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	0.21
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.10
Sift	Benign	0.077	T
Sift4G	Benign	0.19	T
Polyphen		0.31	B
Vest4		0.27
MutPred		0.39		Gain of MoRF binding (P = 0.0055);
MVP		0.54
MPC		0.35
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.30
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-38072218;