rs139156106

chr6-152526149-A-Gchr6-152526149-A-T

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.156T>C(p.Asp52=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00889 in 1,614,130 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (84 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.131

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=-0.6).
• BP6: Variant 6-152526149-A-G is Benign according to our data. Variant chr6-152526149-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 262165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152526149-A-G is described in Lovd as [Likely_benign]. Variant chr6-152526149-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.131 with no splicing effect.
• BS2: High AC in GnomAd at 1133 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.156T>C	p.Asp52=	synonymous_variant	5/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.156T>C	p.Asp52=	synonymous_variant	5/146	1	NM_182961.4	P1

Frequencies

GnomAD3 genomes AF: 0.00744 AC: 1133 AN: 152236 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00721 AC: 1811 AN: 251170 Hom.: 13 AF XY: 0.00712 AC XY: 967 AN XY: 135728

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00904 AC: 13210 AN: 1461776 Hom.: 84 Cov.: 32 AF XY: 0.00891 AC XY: 6480 AN XY: 727200

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00140

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.00758

GnomAD4 genome AF: 0.00744 AC: 1133 AN: 152354 Hom.: 6 Cov.: 32 AF XY: 0.00717 AC XY: 534 AN XY: 74498

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00736 Hom.: 3

Bravo AF: 0.00676

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00966

EpiControl AF: 0.00907

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 22, 2016	- -
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	Mar 02, 2020	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SYNE1: BP4, BP7, BS1, BS2 -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Autosomal recessive ataxia, Beauce type 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. -

SYNE1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2020

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	-0.60
Cadd	Benign	5.8
Dann	Benign	0.56

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs139156106; hg19: chr6-152847284; COSMIC: COSV99584122;