rs121909192

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMN2	NM_017411.4	c.859G>C	p.Gly287Arg	missense_variant	Exon 8 of 9	ENST00000380743.9	NP_059107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMN2	ENST00000380743.9	c.859G>C	p.Gly287Arg	missense_variant	Exon 8 of 9	1	NM_017411.4	ENSP00000370119.4

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

GnomAD3 exomes AF: 0.00332 AC: 751 AN: 226180 Hom.: 132 AF XY: 0.00351 AC XY: 432 AN XY: 123128

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 SAS exome AF: 0.00737

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

Gnomad4 AFR exome AF: 0.000615

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.00290

Gnomad4 EAS exome AF: 0.0000267

Gnomad4 SAS exome AF: 0.00795

Gnomad4 FIN exome AF: 0.000424

Gnomad4 NFE exome AF: 0.00309

Gnomad4 OTH exome AF: 0.00397

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

Gnomad4 AFR AF: 0.000593

Gnomad4 AMR AF: 0.00173

Gnomad4 ASJ AF: 0.00323

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00638

Gnomad4 FIN AF: 0.000218

Gnomad4 NFE AF: 0.00328

Gnomad4 OTH AF: 0.00278

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:2 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Kugelberg-Welander disease Uncertain:1 Benign:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 19, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 28, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variant, NM_017411.3(SMN2):c.859G>C, has been identified in exon 8 of 9 of the SMN2 gene. The variant is predicted to result in a major amino acid change from a glycine to an arginine at position 287 of the protein, NP_059107.1(SMN2):p.(Gly287Arg). The glycine residue at this position has low conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.32% (519 heterozygous, 140 homozygous). The variant has previously been described to have protective effects in patients with spinal muscular atrophy, whereby a milder form of disease was associated with the presence of this variant in one or two copies of SMN2 (ClinVar, Prior, T., et al. (2009), Bernal, C., et al. (2010), Calucho, M. et al. (2018)). Functional analysis in cells expressing this variant demonstrated a restoration of normal full length transcript to approximately 70% of levels present in SMN1 (Prior, T., et al. (2009)). Based on the information available at the time of curation, this variant has been classified as LIKELY BENIGN. -

Spinal muscular atrophy Pathogenic:1

Feb 05, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.859G>C;p.(Gly287Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 7962; OMIM: 601627.0001) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (SMN) - PM1 and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

not specified Benign:1

Mar 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SMN2 c.859G>C (p.Gly287Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0031 in 1464442 control chromosomes in the gnomAD database, including 942 homozygotes (gnomAD database v4.0.0). c.859G>C has been described previously to have protective effects in patients with Spinal Muscular Atrophy. This variant, similar to increased copy numbers of SMN2 gene have been correlated with a milder form of disease (e.g. Bernal_2010, Prior_2009). At least one publication reports a significant increase of exon 7 inclusion from 50% to 70% (Prior_2009), which is in agreement with the reported protective effects. The following publications have been ascertained in the context of this evaluation (PMID: 20577007, 19716110). ClinVar contains an entry for this variant (Variation ID: 7962). Based on the evidence outlined above, the variant was classified as likely benign. -

Spinal muscular atrophy, modifier of Other:1

Sep 01, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N;N;N;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D;D;T;.;.
Sift4G	Benign	0.13	T;T;T;T;T
Vest4		0.29
MutPred		0.79		Gain of MoRF binding (P = 0.0132);.;.;.;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

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

Other links and lift over

dbSNP: rs121909192; hg19: chr5-69372372;