chr21-36699814-T-C

Position:

• chr21-36699814-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000290399.11(SIM2):​c.68T>C​(p.Leu23Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIM2 ENST00000290399.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIM2	NM_005069.6	c.68T>C	p.Leu23Pro	missense_variant	1/11	ENST00000290399.11	NP_005060.1
SIM2	NM_009586.5	c.68T>C	p.Leu23Pro	missense_variant	1/10		NP_033664.2
SIM2	XM_017028442.3	c.68T>C	p.Leu23Pro	missense_variant	1/9		XP_016883931.1
SIM2	XM_047440953.1	c.68T>C	p.Leu23Pro	missense_variant	1/8		XP_047296909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIM2	ENST00000290399.11	c.68T>C	p.Leu23Pro	missense_variant	1/11	1	NM_005069.6	ENSP00000290399	P1
SIM2	ENST00000460783.1	n.682T>C		non_coding_transcript_exon_variant	1/2	1
	ENST00000430607.1	n.269-971A>G		intron_variant, non_coding_transcript_variant		5
SIM2	ENST00000481185.1	n.681T>C		non_coding_transcript_exon_variant	1/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Oct 05, 2023

The c.68T>C (p.L23P) alteration is located in exon 1 (coding exon 1) of the SIM2 gene. This alteration results from a T to C substitution at nucleotide position 68, causing the leucine (L) at amino acid position 23 to be replaced by a proline (P). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.5	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.81		Gain of disorder (P = 0.0221);
MVP		0.77
MPC		1.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.97
gMVP		0.91

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: chr21-38072114;