chr5-70074624-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_017411.4(SMN2):​c.835-1897C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 5 hom., cov: 19)
Failed GnomAD Quality Control

Consequence

SMN2
NM_017411.4 intron

Scores

2

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.192
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMN2NM_017411.4 linkc.835-1897C>T intron_variant Intron 7 of 8 ENST00000380743.9 NP_059107.1 Q16637-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMN2ENST00000380743.9 linkc.835-1897C>T intron_variant Intron 7 of 8 1 NM_017411.4 ENSP00000370119.4 Q16637-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
378
AN:
125674
Hom.:
5
Cov.:
19
FAILED QC
Gnomad AFR
AF:
0.000821
Gnomad AMI
AF:
0.0161
Gnomad AMR
AF:
0.00100
Gnomad ASJ
AF:
0.00241
Gnomad EAS
AF:
0.000447
Gnomad SAS
AF:
0.00336
Gnomad FIN
AF:
0.00347
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00475
Gnomad OTH
AF:
0.00119
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00301
AC:
378
AN:
125774
Hom.:
5
Cov.:
19
AF XY:
0.00284
AC XY:
172
AN XY:
60628
show subpopulations
Gnomad4 AFR
AF:
0.000818
Gnomad4 AMR
AF:
0.00100
Gnomad4 ASJ
AF:
0.00241
Gnomad4 EAS
AF:
0.000447
Gnomad4 SAS
AF:
0.00336
Gnomad4 FIN
AF:
0.00347
Gnomad4 NFE
AF:
0.00475
Gnomad4 OTH
AF:
0.00117
Alfa
AF:
0.00205
Hom.:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Werdnig-Hoffmann disease Uncertain:1
-
Area of Clinical and Molecular Genetics, Hospital Universitario Vall de Hebron
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.88
CADD
Benign
3.2
DANN
Benign
0.88

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.

Other links and lift over

dbSNP: rs1381625877; hg19: chr5-69370451; API