21-36719859-T-C

Variant names:

• chr21-36719859-T-C
• rs147054081
• NM_005069.6:c.387T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4 BP6_Very_Strong BP7 BS2

The NM_005069.6(SIM2):​c.387T>C​(p.His129His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,612,770 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (27 hom.)
• Consequence: SIM2 NM_005069.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.50
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.257).
• BP6: Variant 21-36719859-T-C is Benign according to our data. Variant chr21-36719859-T-C is described in ClinVar as Benign. ClinVar VariationId is 779193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 27 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005069.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM2	NM_005069.6	MANE Select	c.387T>C	p.His129His	synonymous	Exon 4 of 11	NP_005060.1	Q14190-1
	SIM2	NM_009586.5		c.387T>C	p.His129His	synonymous	Exon 4 of 10	NP_033664.2	Q14190-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM2	ENST00000290399.11	TSL:1 MANE Select	c.387T>C	p.His129His	synonymous	Exon 4 of 11	ENSP00000290399.6	Q14190-1
	SIM2	ENST00000431229.1	TSL:1	c.198T>C	p.His66His	synonymous	Exon 3 of 10	ENSP00000392003.1	H7BZX8
	SIM2	ENST00000483178.2	TSL:3	c.96T>C	p.His32His	synonymous	Exon 2 of 2	ENSP00000476273.1	V9GY04

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 458 AN: 151440 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000535

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00835

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.00792

Gnomad FIN AF: 0.00220

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00513 AC: 1291 AN: 251442 AF XY: 0.00529

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.00329

Gnomad NFE exome AF: 0.00424

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00400 AC: 5840 AN: 1461212 Hom.: 27 Cov.: 31 AF XY: 0.00424 AC XY: 3079 AN XY: 726966

African (AFR) AF: 0.000448 AC: 15 AN: 33468

American (AMR) AF: 0.0120 AC: 536 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39698

South Asian (SAS) AF: 0.00953 AC: 822 AN: 86240

European-Finnish (FIN) AF: 0.00418 AC: 223 AN: 53350

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5762

European-Non Finnish (NFE) AF: 0.00359 AC: 3995 AN: 1111466

Other (OTH) AF: 0.00363 AC: 219 AN: 60376

GnomAD4 genome AF: 0.00302 AC: 458 AN: 151558 Hom.: 1 Cov.: 32 AF XY: 0.00327 AC XY: 242 AN XY: 74014

African (AFR) AF: 0.000534 AC: 22 AN: 41234

American (AMR) AF: 0.00834 AC: 127 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5158

South Asian (SAS) AF: 0.00793 AC: 38 AN: 4794

European-Finnish (FIN) AF: 0.00220 AC: 23 AN: 10460

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00350 AC: 238 AN: 67916

Other (OTH) AF: 0.00143 AC: 3 AN: 2102

Alfa AF: 0.00286 Hom.: 1

Bravo AF: 0.00310

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00403

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.8
DANN	Benign	0.66
PhyloP100		-1.5
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147054081; hg19: chr21-38092160;