rs2747662

Positions:

• chr6-152145539-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001347702.2(SYNE1):​c.1458A>G​(p.Glu486=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 1,612,136 control chromosomes in the GnomAD database, including 89,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (8863 hom., cov: 31)
  • Exomes 𝑓: 0.33 (80854 hom.)
• Consequence: SYNE1 NM_001347702.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.569

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 6-152145539-T-C is Benign according to our data. Variant chr6-152145539-T-C is described in ClinVar as [Benign]. Clinvar id is 130429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152145539-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.569 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_001347702.2	c.1458A>G	p.Glu486=	synonymous_variant	9/18	ENST00000354674.5	NP_001334631.1
SYNE1	NM_182961.4	c.24977-1774A>G		intron_variant		ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000354674.5	c.1458A>G	p.Glu486=	synonymous_variant	9/18	5	NM_001347702.2	ENSP00000346701
SYNE1	ENST00000367255.10	c.24977-1774A>G		intron_variant		1	NM_182961.4	ENSP00000356224	P1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51144 AN: 151794 Hom.: 8857 Cov.: 31

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.386

GnomAD3 exomes AF: 0.352 AC: 88527 AN: 251410 Hom.: 16619 AF XY: 0.350 AC XY: 47580 AN XY: 135878

Gnomad AFR exome AF: 0.342

Gnomad AMR exome AF: 0.504

Gnomad ASJ exome AF: 0.400

Gnomad EAS exome AF: 0.301

Gnomad SAS exome AF: 0.412

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.320

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.329 AC: 480152 AN: 1460224 Hom.: 80854 Cov.: 34 AF XY: 0.331 AC XY: 240302 AN XY: 726490

Gnomad4 AFR exome AF: 0.329

Gnomad4 AMR exome AF: 0.498

Gnomad4 ASJ exome AF: 0.401

Gnomad4 EAS exome AF: 0.309

Gnomad4 SAS exome AF: 0.407

Gnomad4 FIN exome AF: 0.220

Gnomad4 NFE exome AF: 0.319

Gnomad4 OTH exome AF: 0.339

GnomAD4 genome AF: 0.337 AC: 51185 AN: 151912 Hom.: 8863 Cov.: 31 AF XY: 0.338 AC XY: 25068 AN XY: 74244

Gnomad4 AFR AF: 0.335

Gnomad4 AMR AF: 0.458

Gnomad4 ASJ AF: 0.401

Gnomad4 EAS AF: 0.310

Gnomad4 SAS AF: 0.401

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.323

Gnomad4 OTH AF: 0.384

Alfa AF: 0.342 Hom.: 11590

Bravo AF: 0.357

Asia WGS AF: 0.345 AC: 1198 AN: 3476

EpiCase AF: 0.330

EpiControl AF: 0.335

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 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. -

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

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 02, 2018

- -

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. -

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	-0.25
CADD	Benign	13
DANN	Benign	0.61

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2747662; hg19: chr6-152466674; COSMIC: COSV54911291; COSMIC: COSV54911291;