rs104893928

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP5

The NM_017411.4(SMN2):c.5C>G(p.Ala2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in UniProt as Likely_pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 3)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SMN2
NM_017411.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.58

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a modified_residue N-acetylalanine (size 0) in uniprot entity SMN_HUMAN

PP5

Variant 5-70049690-C-G is Pathogenic according to our data. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null. Variant chr5-70049690-C-G is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMN2	NM_017411.4 link	c.5C>G	p.Ala2Gly	missense_variant	1/9	ENST00000380743.9	NP_059107.1	Q16637-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMN2	ENST00000380743.9 link	c.5C>G	p.Ala2Gly	missense_variant	1/9	1	NM_017411.4	ENSP00000370119.4		Q16637-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

9918

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000357

AC:

AN:

28012

Hom.:

AF XY:

0.00

AC XY:

AN XY:

14820

show subpopulations

Gnomad AFR exome

AF:

0.000510

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

193112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

102140

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

9918

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

4158

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Benign

0.13

Eigen_PC

Benign

0.029

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.81

.;.;.;.;T;.;.;.

M_CAP

Pathogenic

0.63

MetaRNN

Uncertain

0.60

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.65

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.88

N;N;.;N;.;.;.;N

REVEL

Uncertain

0.61

Sift

Uncertain

0.020

D;D;.;D;.;.;.;D

Sift4G

Uncertain

0.039

D;T;D;D;.;D;D;D

Vest4

0.41

MutPred

0.67

Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);

MVP

0.94

MPC

2.6

ClinPred

0.14

GERP RS

2.5

gMVP

0.50

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