rs62427038

Positions:

• chr6-152465312-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_182961.4(SYNE1):​c.1878A>G​(p.Gln626=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00739 in 1,613,854 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (65 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.675

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 6-152465312-T-C is Benign according to our data. Variant chr6-152465312-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 194900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152465312-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.675 with no splicing effect.
• BS2: High AC in GnomAd4 at 708 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.1878A>G	p.Gln626=	synonymous_variant	18/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.1878A>G	p.Gln626=	synonymous_variant	18/146	1	NM_182961.4	P1

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 707 AN: 152160 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00853

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00515 AC: 1293 AN: 250982 Hom.: 9 AF XY: 0.00536 AC XY: 727 AN XY: 135638

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.00909

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00767 AC: 11214 AN: 1461576 Hom.: 65 Cov.: 32 AF XY: 0.00761 AC XY: 5536 AN XY: 727086

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00282

Gnomad4 FIN exome AF: 0.00425

Gnomad4 NFE exome AF: 0.00920

Gnomad4 OTH exome AF: 0.00614

GnomAD4 genome AF: 0.00465 AC: 708 AN: 152278 Hom.: 2 Cov.: 32 AF XY: 0.00424 AC XY: 316 AN XY: 74462

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00853

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00727 Hom.: 3

Bravo AF: 0.00442

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00698

EpiControl AF: 0.00853

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 17, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SYNE1: BP4, BP7, BS2 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Autosomal recessive ataxia, Beauce type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

SYNE1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.1
DANN	Benign	0.66

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs62427038; hg19: chr6-152786447;