rs139834542

chr6-152133421-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PP2 PP3 BP4_Moderate BP6 BS2

The NM_182961.4(SYNE1):c.25856T>C(p.Leu8619Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,614,194 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (5 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:9
• Conservation: PhyloP100: 9.32

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SYNE1
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.1274248).
• BP6: Variant 6-152133421-A-G is Benign according to our data. Variant chr6-152133421-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282403.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4, Benign=1}. Variant chr6-152133421-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 264 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.25856T>C	p.Leu8619Pro	missense_variant	143/146	ENST00000367255.10
SYNE1	NM_001347702.2	c.2390T>C	p.Leu797Pro	missense_variant	15/18	ENST00000354674.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.25856T>C	p.Leu8619Pro	missense_variant	143/146	1	NM_182961.4	P1
SYNE1	ENST00000354674.5	c.2390T>C	p.Leu797Pro	missense_variant	15/18	5	NM_001347702.2

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 264 AN: 152202 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00130 AC: 328 AN: 251466 Hom.: 1 AF XY: 0.00139 AC XY: 189 AN XY: 135908

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00253 AC: 3693 AN: 1461874 Hom.: 5 Cov.: 31 AF XY: 0.00250 AC XY: 1817 AN XY: 727238

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00315

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00173 AC: 264 AN: 152320 Hom.: 1 Cov.: 33 AF XY: 0.00172 AC XY: 128 AN XY: 74480

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00290

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00247 Hom.: 2

Bravo AF: 0.00169

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00123 AC: 149

EpiCase AF: 0.00273

EpiControl AF: 0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 16, 2023	BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	SYNE1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2018	The SYNE1 c.25712T>C; p.Leu8571Pro variant (rs139834542, ClinVar variant ID 282403), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.2% (identified on 315 out of 126,708 chromosomes, including one homozygote). The leucine at position 8571 is weakly conserved, considering 12 species, and computational analyses of the effects of the p.Leu8571Pro variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Based on the available information, the clinical significance of the p.Leu8571Pro variant cannot be determined with certainty. -

Autosomal recessive ataxia, Beauce type Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 28, 2021

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

SYNE1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2021

This variant is classified as likely 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
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Pathogenic	0.26
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;.;T;T;T;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	3.3	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-6.5	D;D;D;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.98
MVP		0.87
MPC		0.78
ClinPred		0.15	T
GERP RS		5.6
Varity_R		0.91
gMVP		0.88

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs139834542; hg19: chr6-152454556; COSMIC: COSV55076730; COSMIC: COSV55076730;