Genetic Variant NM_005069.6:c.457+99G>A (chr21-36720028-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -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

Publications

1 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM2	NM_005069.6	MANE Select	c.457+99G>A		intron	N/A	NP_005060.1
	SIM2	NM_009586.5		c.457+99G>A		intron	N/A	NP_033664.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SIM2	ENST00000290399.11	TSL:1 MANE Select	c.457+99G>A	intron	N/A	ENSP00000290399.6
SIM2	ENST00000431229.1	TSL:1	c.268+99G>A	intron	N/A	ENSP00000392003.1
SIM2	ENST00000483178.2	TSL:3	c.*43G>A	3_prime_UTR	Exon 2 of 2	ENSP00000476273.1

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

GnomAD2 exomes

AF:

0.00249

AC:

468

AN:

188004

AF XY:

0.00175

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 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

African (AFR)

AF:

0.0320

AC:

586

AN:

18298

American (AMR)

AF:

0.00149

AC:

AN:

38324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19998

East Asian (EAS)

AF:

0.00

AC:

AN:

35920

South Asian (SAS)

AF:

0.0000443

AC:

AN:

67656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36794

Middle Eastern (MID)

AF:

0.00166

AC:

AN:

4214

European-Non Finnish (NFE)

AF:

0.0000460

AC:

AN:

434912

Other (OTH)

AF:

0.00257

AC:

AN:

35070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

117

156

195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00948

AC:

1441

AN:

152064

Hom.:

Cov.:

AF XY:

0.00885

AC XY:

658

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0331

AC:

1374

AN:

41472

American (AMR)

AF:

0.00275

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67996

Other (OTH)

AF:

0.00712

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

144

216

288

360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.49

(source)

DANN

Benign

0.76

PhyloP100

-0.67

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over