rs1554558620

Positions:

• chr6-152208032-ACTCATGGGGAGGTAGGACACTTCAACCAACCATTTACGAAGCTTTTCTGCCATCT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_182961.4(SYNE1):​c.22709_22763del​(p.Glu7570ValfsTer36) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SYNE1 NM_182961.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.96

Genes affected

SYNE1 (HGNC:17089): (spectrin repeat containing nuclear envelope protein 1) This gene encodes a spectrin repeat containing protein expressed in skeletal and smooth muscle, and peripheral blood lymphocytes, that localizes to the nuclear membrane. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia 8, also referred to as autosomal recessive cerebellar ataxia type 1 or recessive ataxia of Beauce. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-152208032-ACTCATGGGGAGGTAGGACACTTCAACCAACCATTTACGAAGCTTTTCTGCCATCT-A is Pathogenic according to our data. Variant chr6-152208032-ACTCATGGGGAGGTAGGACACTTCAACCAACCATTTACGAAGCTTTTCTGCCATCT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 448583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152208032-ACTCATGGGGAGGTAGGACACTTCAACCAACCATTTACGAAGCTTTTCTGCCATCT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.22709_22763del	p.Glu7570ValfsTer36	frameshift_variant	125/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.22709_22763del	p.Glu7570ValfsTer36	frameshift_variant	125/146	1	NM_182961.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 17, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2018	A variant that is likely pathogenic has been identified in the SYNE1 gene. The c.22496_22550del55 variant in the SYNE1 gene causes a frameshift starting with codon Glutamic acid 7499, changes this amino acid to a Valine residue and creates a premature Stop codon at position 36 of the new reading frame, denoted p.Glu7499ValfsX36. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554558620; hg19: chr6-152529167;