rs4916

Positions:

• chr5-70076526-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_017411.4(SMN2):​c.840T>C​(p.Phe280=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000073 (15 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMN2 NM_017411.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.459

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP7: Synonymous conserved (PhyloP=0.459 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMN2	NM_017411.4	c.840T>C	p.Phe280=	synonymous_variant	8/9	ENST00000380743.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMN2	ENST00000380743.9	c.840T>C	p.Phe280=	synonymous_variant	8/9	1	NM_017411.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 17 AN: 129458 Hom.: 0 Cov.: 19 FAILED QC

Gnomad AFR AF: 0.000426

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000782

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: 0.0000486

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000727 AC: 97 AN: 1334670 Hom.: 15 Cov.: 29 AF XY: 0.0000631 AC XY: 42 AN XY: 665344

Gnomad4 AFR exome AF: 0.000539

Gnomad4 AMR exome AF: 0.0000739

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000615

Gnomad4 SAS exome AF: 0.0000739

Gnomad4 FIN exome AF: 0.000141

Gnomad4 NFE exome AF: 0.0000344

Gnomad4 OTH exome AF: 0.0000907

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000131 AC: 17 AN: 129542 Hom.: 0 Cov.: 19 AF XY: 0.0000794 AC XY: 5 AN XY: 62934

Gnomad4 AFR AF: 0.000425

Gnomad4 AMR AF: 0.0000782

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000486

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	14
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs4916; hg19: chr5-69372353;