5-70076545-G-C

Variant names:

• chr5-70076545-G-C
• rs121909192
• NM_017411.4:c.859G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_017411.4(SMN2):​c.859G>C​(p.Gly287Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,464,442 control chromosomes in the GnomAD database, including 942 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (54 hom., cov: 19)
  • Exomes 𝑓: 0.0032 (888 hom.)
• Consequence: SMN2 NM_017411.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:2 O:2
• Conservation: PhyloP100: 2.78
• Publications: 103 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0688639).
• BS2: High AC in GnomAd4 at 288 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMN2	NM_017411.4	MANE Select	c.859G>C	p.Gly287Arg	missense	Exon 8 of 9	NP_059107.1
	SMN2	NM_022876.2		c.763G>C	p.Gly255Arg	missense	Exon 7 of 8	NP_075014.1	Q16637-2
	SMN2	NM_022875.3		c.835-474G>C		intron	N/A	NP_075013.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMN2	ENST00000380743.9	TSL:1 MANE Select	c.859G>C	p.Gly287Arg	missense	Exon 8 of 9	ENSP00000370119.4	Q16637-1
	SMN2	ENST00000380741.8	TSL:1	c.859G>C	p.Gly287Arg	missense	Exon 8 of 8	ENSP00000370117.5	Q16637-1
	SMN2	ENST00000626847.2	TSL:1	c.835-474G>C		intron	N/A	ENSP00000486152.1	Q16637-3

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 289 AN: 128726 Hom.: 54 Cov.: 19

Gnomad AFR AF: 0.000595

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00174

Gnomad ASJ AF: 0.00323

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00638

Gnomad FIN AF: 0.000218

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.00281

GnomAD2 exomes AF: 0.00332 AC: 751 AN: 226180 AF XY: 0.00351

Gnomad AFR exome AF: 0.000563

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00276

Gnomad EAS exome AF: 0.0000573

Gnomad FIN exome AF: 0.000348

Gnomad NFE exome AF: 0.00412

Gnomad OTH exome AF: 0.00235

GnomAD4 exome AF: 0.00322 AC: 4295 AN: 1335624 Hom.: 888 Cov.: 29 AF XY: 0.00338 AC XY: 2250 AN XY: 665758

African (AFR) AF: 0.000615 AC: 16 AN: 26020

American (AMR) AF: 0.00242 AC: 98 AN: 40518

Ashkenazi Jewish (ASJ) AF: 0.00290 AC: 68 AN: 23482

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37498

South Asian (SAS) AF: 0.00795 AC: 645 AN: 81136

European-Finnish (FIN) AF: 0.000424 AC: 21 AN: 49520

Middle Eastern (MID) AF: 0.0156 AC: 84 AN: 5384

European-Non Finnish (NFE) AF: 0.00309 AC: 3143 AN: 1016914

Other (OTH) AF: 0.00397 AC: 219 AN: 55152

GnomAD4 genome AF: 0.00224 AC: 288 AN: 128818 Hom.: 54 Cov.: 19 AF XY: 0.00242 AC XY: 151 AN XY: 62484

African (AFR) AF: 0.000593 AC: 18 AN: 30364

American (AMR) AF: 0.00173 AC: 22 AN: 12686

Ashkenazi Jewish (ASJ) AF: 0.00323 AC: 10 AN: 3098

East Asian (EAS) AF: 0.00 AC: 0 AN: 4786

South Asian (SAS) AF: 0.00638 AC: 27 AN: 4234

European-Finnish (FIN) AF: 0.000218 AC: 2 AN: 9176

Middle Eastern (MID) AF: 0.00719 AC: 2 AN: 278

European-Non Finnish (NFE) AF: 0.00328 AC: 202 AN: 61520

Other (OTH) AF: 0.00278 AC: 5 AN: 1796

Alfa AF: 0.00211 Hom.: 3

ESP6500AA AF: 0.000826 AC: 3

ESP6500EA AF: 0.00478 AC: 38

ExAC AF: 0.00336 AC: 379

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Kugelberg-Welander disease (3)
-	-	1	not specified (1)
1	-	-	Spinal muscular atrophy (1)
-	-	-	Spinal muscular atrophy, modifier of (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.74	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.069	T
MetaSVM	Pathogenic	1.1	D
PhyloP100		2.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.13	T
Vest4		0.29
MutPred		0.79		Gain of MoRF binding (P = 0.0132)
MVP		0.95
MPC		4.0
ClinPred		0.026	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
gMVP		0.59
Mutation Taster		=82/18	disease causing (ClinVar)

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: rs121909192; hg19: chr5-69372372;