chr5-70074624-C-T

Variant names:

• chr5-70074624-C-T
• rs1381625877
• NM_017411.4:c.835-1897C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_017411.4(SMN2):​c.835-1897C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (5 hom., cov: 19)
  • Failed GnomAD Quality Control
• Consequence: SMN2 NM_017411.4 intron
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.192

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMN2	NM_017411.4	c.835-1897C>T		intron_variant	Intron 7 of 8	ENST00000380743.9	NP_059107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMN2	ENST00000380743.9	c.835-1897C>T		intron_variant	Intron 7 of 8	1	NM_017411.4	ENSP00000370119.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 378 AN: 125674 Hom.: 5 Cov.: 19 FAILED QC

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.0161

Gnomad AMR AF: 0.00100

Gnomad ASJ AF: 0.00241

Gnomad EAS AF: 0.000447

Gnomad SAS AF: 0.00336

Gnomad FIN AF: 0.00347

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00119

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

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00301 AC: 378 AN: 125774 Hom.: 5 Cov.: 19 AF XY: 0.00284 AC XY: 172 AN XY: 60628

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00100

Gnomad4 ASJ AF: 0.00241

Gnomad4 EAS AF: 0.000447

Gnomad4 SAS AF: 0.00336

Gnomad4 FIN AF: 0.00347

Gnomad4 NFE AF: 0.00475

Gnomad4 OTH AF: 0.00117

Alfa AF: 0.00205 Hom.: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Werdnig-Hoffmann disease Uncertain:1

-

Area of Clinical and Molecular Genetics, Hospital Universitario Vall de Hebron

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.2
DANN	Benign	0.88

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: rs1381625877; hg19: chr5-69370451;