chr5-70076555-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_017411.4(SMN2):c.869C>G(p.Ser290*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,463,808 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00047 ( 21 hom., cov: 19)

Exomes 𝑓: 0.000088 ( 40 hom. )

Consequence

SMN2
NM_017411.4 stop_gained

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.15

Publications

1 publications found

Variant links:

Genes affected

SMN2 (HGNC:11118): (survival of motor neuron 2, centromeric) This gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. The telomeric and centromeric copies of this gene are nearly identical and encode the same protein. While mutations in the telomeric copy are associated with spinal muscular atrophy, mutations in this gene, the centromeric copy, do not lead to disease. This gene may be a modifier of disease caused by mutation in the telomeric copy. The critical sequence difference between the two genes is a single nucleotide in exon 7, which is thought to be an exon splice enhancer. Note that the nine exons of both the telomeric and centromeric copies are designated historically as exon 1, 2a, 2b, and 3-8. It is thought that gene conversion events may involve the two genes, leading to varying copy numbers of each gene. The full length protein encoded by this gene localizes to both the cytoplasm and the nucleus. Within the nucleus, the protein localizes to subnuclear bodies called gems which are found near coiled bodies containing high concentrations of small ribonucleoproteins (snRNPs). This protein forms heteromeric complexes with proteins such as SIP1 and GEMIN4, and also interacts with several proteins known to be involved in the biogenesis of snRNPs, such as hnRNP U protein and the small nucleolar RNA binding protein. Four transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Sep 2008]

SMN2 Gene-Disease associations (from GenCC):

spinal muscular atrophy, type III
Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia

SMN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 5-70076555-C-G is Benign according to our data. Variant chr5-70076555-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3362672.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 60 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017411.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMN2	NM_017411.4	MANE Select	c.869C>G	p.Ser290*	stop_gained	Exon 8 of 9	NP_059107.1
SMN2	NM_022876.2		c.773C>G	p.Ser258*	stop_gained	Exon 7 of 8	NP_075014.1	Q16637-2
SMN2	NM_022875.3		c.835-464C>G		intron	N/A	NP_075013.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMN2	ENST00000380743.9	TSL:1 MANE Select	c.869C>G	p.Ser290*	stop_gained	Exon 8 of 9	ENSP00000370119.4	Q16637-1
SMN2	ENST00000380741.8	TSL:1	c.869C>G	p.Ser290*	stop_gained	Exon 8 of 8	ENSP00000370117.5	Q16637-1
SMN2	ENST00000626847.2	TSL:1	c.835-464C>G		intron	N/A	ENSP00000486152.1	Q16637-3

Frequencies

GnomAD3 genomes

AF:

0.000466

AC:

AN:

128672

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000129

AC:

AN:

225648

AF XY:

0.000130

show subpopulations

Gnomad AFR exome

AF:

0.00193

Gnomad AMR exome

AF:

0.0000642

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000984

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000876

AC:

117

AN:

1335136

Hom.:

Cov.:

AF XY:

0.0000871

AC XY:

AN XY:

665532

show subpopulations

African (AFR)

AF:

0.00339

AC:

AN:

25990

American (AMR)

AF:

0.0000741

AC:

AN:

40496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23490

East Asian (EAS)

AF:

0.00

AC:

AN:

37500

South Asian (SAS)

AF:

0.0000862

AC:

AN:

81168

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49530

Middle Eastern (MID)

AF:

0.000742

AC:

AN:

5392

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1016438

Other (OTH)

AF:

0.000272

AC:

AN:

55132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.420

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000466

AC:

AN:

128672

Hom.:

Cov.:

AF XY:

0.000433

AC XY:

AN XY:

62374

show subpopulations

African (AFR)

AF:

0.00198

AC:

AN:

30242

American (AMR)

AF:

0.00

AC:

AN:

12670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3086

East Asian (EAS)

AF:

0.00

AC:

AN:

4796

South Asian (SAS)

AF:

0.00

AC:

AN:

4222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

61514

Other (OTH)

AF:

0.00

AC:

AN:

1780

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000337

Hom.:

ESP6500AA

AF:

0.00165

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000231

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Kugelberg-Welander disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Uncertain

0.47

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.48

PhyloP100

1.2

Vest4

0.73

GERP RS

0.30

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=141/59

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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