Variant chr21-36720028-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_005069.6(SIM2):c.457+99G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 843,250 control chromosomes in the GnomAD database, including 35 homozygotes. 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: 𝑓 0.0095 ( 21 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 14 hom. )

Consequence

SIM2
NM_005069.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.666

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]

SIM2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00948 (1441/152064) while in subpopulation AFR AF= 0.0331 (1374/41472). AF 95% confidence interval is 0.0317. There are 21 homozygotes in gnomad4. There are 658 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIM2	NM_005069.6 linkuse as main transcript	c.457+99G>A		intron_variant		ENST00000290399.11

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIM2	ENST00000290399.11 linkuse as main transcript	c.457+99G>A	intron_variant		1	NM_005069.6	P1	Q14190-1
SIM2	ENST00000431229.1 linkuse as main transcript	c.269+99G>A	intron_variant		1
SIM2	ENST00000483178.2 linkuse as main transcript	c.*43G>A	3_prime_UTR_variant	2/2	3
SIM2	ENST00000481185.1 linkuse as main transcript	n.1070+99G>A	intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00946

AC:

1437

AN:

151960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00719

GnomAD3 exomes

AF:

0.00249

AC:

468

AN:

188004

Hom.:

AF XY:

0.00175

AC XY:

181

AN XY:

103536

show subpopulations

Gnomad AFR exome

AF:

0.0364

Gnomad AMR exome

AF:

0.00158

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000817

Gnomad OTH exome

AF:

0.000630

GnomAD4 exome

AF:

0.00110

AC:

763

AN:

691186

Hom.:

Cov.:

AF XY:

0.000923

AC XY:

340

AN XY:

368288

show subpopulations

Gnomad4 AFR exome

AF:

0.0320

Gnomad4 AMR exome

AF:

0.00149

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000443

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000460

Gnomad4 OTH exome

AF:

0.00257

GnomAD4 genome

AF:

0.00948

AC:

1441

AN:

152064

Hom.:

Cov.:

AF XY:

0.00885

AC XY:

658

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0331

Gnomad4 AMR

AF:

0.00275

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00712

Alfa

AF:

0.00577

Hom.:

Bravo

AF:

0.0106

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.49

DANN

Benign

0.76

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over