NM_017411.4:c.5_6delCGinsGC

Variant names:

• chr5-70049690-CG-GC
• NM_017411.4:c.5_6delCGinsGC
• SMN2 p.Ala2Gly

Variant summary

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

The NM_017411.4(SMN2):​c.5_6delCGinsGC​(p.Ala2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 3)
• Consequence: SMN2 NM_017411.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58
• Publications: 0 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.5_6delCGinsGC	p.Ala2Gly	missense	N/A	NP_059107.1
	SMN2	NM_022875.3		c.5_6delCGinsGC	p.Ala2Gly	missense	N/A	NP_075013.1
	SMN2	NM_022876.2		c.5_6delCGinsGC	p.Ala2Gly	missense	N/A	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.5_6delCGinsGC	p.Ala2Gly	missense	N/A	ENSP00000370119.4	Q16637-1
	SMN2	ENST00000380741.8	TSL:1	c.5_6delCGinsGC	p.Ala2Gly	missense	N/A	ENSP00000370117.5	Q16637-1
	SMN2	ENST00000626847.2	TSL:1	c.5_6delCGinsGC	p.Ala2Gly	missense	N/A	ENSP00000486152.1	Q16637-3

Frequencies

GnomAD3 genomes Cov.: 3

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-69345517;