rs2252748

chr6-152148196-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182961.4(SYNE1):c.24825G>A(p.Pro8275=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,613,768 control chromosomes in the GnomAD database, including 72,346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7130 hom., cov: 32)
  • Exomes 𝑓: 0.29 (65216 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.11

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 6-152148196-C-T is Benign according to our data. Variant chr6-152148196-C-T is described in ClinVar as [Benign]. Clinvar id is 130427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152148196-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.24825G>A	p.Pro8275=	synonymous_variant	137/146	ENST00000367255.10
SYNE1	NM_001347702.2	c.1290G>A	p.Pro430=	synonymous_variant	8/18	ENST00000354674.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.24825G>A	p.Pro8275=	synonymous_variant	137/146	1	NM_182961.4	P1
SYNE1	ENST00000354674.5	c.1290G>A	p.Pro430=	synonymous_variant	8/18	5	NM_001347702.2

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45848 AN: 151942 Hom.: 7124 Cov.: 32

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.336

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.331

GnomAD3 exomes AF: 0.320 AC: 80254 AN: 251104 Hom.: 13895 AF XY: 0.318 AC XY: 43165 AN XY: 135734

Gnomad AFR exome AF: 0.309

Gnomad AMR exome AF: 0.473

Gnomad ASJ exome AF: 0.338

Gnomad EAS exome AF: 0.301

Gnomad SAS exome AF: 0.401

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.317

GnomAD4 exome AF: 0.294 AC: 430304 AN: 1461708 Hom.: 65216 Cov.: 40 AF XY: 0.297 AC XY: 215936 AN XY: 727152

Gnomad4 AFR exome AF: 0.298

Gnomad4 AMR exome AF: 0.466

Gnomad4 ASJ exome AF: 0.337

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.396

Gnomad4 FIN exome AF: 0.180

Gnomad4 NFE exome AF: 0.283

Gnomad4 OTH exome AF: 0.301

GnomAD4 genome AF: 0.302 AC: 45889 AN: 152060 Hom.: 7130 Cov.: 32 AF XY: 0.303 AC XY: 22506 AN XY: 74336

Gnomad4 AFR AF: 0.304

Gnomad4 AMR AF: 0.411

Gnomad4 ASJ AF: 0.336

Gnomad4 EAS AF: 0.312

Gnomad4 SAS AF: 0.389

Gnomad4 FIN AF: 0.175

Gnomad4 NFE AF: 0.286

Gnomad4 OTH AF: 0.329

Alfa AF: 0.296 Hom.: 12151

Bravo AF: 0.322

Asia WGS AF: 0.337 AC: 1170 AN: 3478

EpiCase AF: 0.290

EpiControl AF: 0.291

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Autosomal recessive ataxia, Beauce type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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	-0.63
Cadd	Benign	0.16
Dann	Benign	0.71

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2252748; hg19: chr6-152469331; COSMIC: COSV54964871; COSMIC: COSV54964871;