chr5-70049690-C-G

Variant names:

• chr5-70049690-C-G
• rs75030631
• NM_017411.4:c.5C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_017411.4(SMN2):​c.5C>G​(p.Ala2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58
• Publications: 8 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMN2	NM_017411.4	MANE Select	c.5C>G	p.Ala2Gly	missense	Exon 1 of 9	NP_059107.1
	SMN2	NM_022875.3		c.5C>G	p.Ala2Gly	missense	Exon 1 of 8	NP_075013.1
	SMN2	NM_022876.2		c.5C>G	p.Ala2Gly	missense	Exon 1 of 8	NP_075014.1	Q16637-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMN2	ENST00000380743.9	TSL:1 MANE Select	c.5C>G	p.Ala2Gly	missense	Exon 1 of 9	ENSP00000370119.4	Q16637-1
	SMN2	ENST00000380741.8	TSL:1	c.5C>G	p.Ala2Gly	missense	Exon 1 of 8	ENSP00000370117.5	Q16637-1
	SMN2	ENST00000626847.2	TSL:1	c.5C>G	p.Ala2Gly	missense	Exon 1 of 8	ENSP00000486152.1	Q16637-3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 9918 Hom.: 0 Cov.: 3

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

GnomAD2 exomes AF: 0.0000357 AC: 1 AN: 28012 AF XY: 0.00

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 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: 0 AN: 193112 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 102140

African (AFR) AF: 0.00 AC: 0 AN: 4402

American (AMR) AF: 0.00 AC: 0 AN: 9346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4950

East Asian (EAS) AF: 0.00 AC: 0 AN: 10854

South Asian (SAS) AF: 0.00 AC: 0 AN: 31282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 112152

Other (OTH) AF: 0.00 AC: 0 AN: 10262

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 9918 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 4158

African (AFR) AF: 0.00 AC: 0 AN: 1074

American (AMR) AF: 0.00 AC: 0 AN: 1220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 228

East Asian (EAS) AF: 0.00 AC: 0 AN: 892

South Asian (SAS) AF: 0.00 AC: 0 AN: 648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 86

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 5238

Other (OTH) AF: 0.00 AC: 0 AN: 188

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Benign	0.13
Eigen_PC	Benign	0.029
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.65	D
PhyloP100		2.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.039	D
Vest4		0.41
MutPred		0.67		Loss of sheet (P = 0.0457)
MVP		0.94
MPC		2.6
ClinPred		0.14	T
GERP RS		2.5
PromoterAI		-0.13	Neutral
gMVP		0.50
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs75030631; hg19: chr5-69345517;