rs119103248

chr6-152140027-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_182961.4(SYNE1):c.25381G>A(p.Glu8461Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000834 in 1,614,192 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E8461E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (2 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:7
• Conservation: PhyloP100: 3.41

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 -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SYNE1
• BP4: Computational evidence support a benign effect (MetaRNN=0.02014187).
• BS2: High AC in GnomAd at 122 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.25381G>A	p.Glu8461Lys	missense_variant	140/146	ENST00000367255.10
SYNE1	NM_001347702.2	c.1915G>A	p.Glu639Lys	missense_variant	12/18	ENST00000354674.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.25381G>A	p.Glu8461Lys	missense_variant	140/146	1	NM_182961.4	P1
SYNE1	ENST00000354674.5	c.1915G>A	p.Glu639Lys	missense_variant	12/18	5	NM_001347702.2

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000668 AC: 168 AN: 251482 Hom.: 0 AF XY: 0.000699 AC XY: 95 AN XY: 135920

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000818

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000837 AC: 1224 AN: 1461890 Hom.: 2 Cov.: 33 AF XY: 0.000864 AC XY: 628 AN XY: 727248

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000950

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000738 AC XY: 55 AN XY: 74478

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000797 Hom.: 0

Bravo AF: 0.00102

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000585 AC: 71

EpiCase AF: 0.00120

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2018	The SYNE1 c.25237G>A; p.Glu8413Lys variant (rs119103248), also reported as c.2132G>A; p.Glu646Lys for a shorter alternate transcript by Zhang et al. (2007), was identified in an individual with Emery-Dreifuss Muscular Dystrophy-like symptoms; however, it has not been demonstrated to be disease-causing (Zhang 2007). This variant is reported in ClinVar (Variation ID: 2334) and is found in the Latino population with an overall allele frequency of 0.16% (55/34420 alleles) in the Genome Aggregation Database. The glutamate at codon 8413 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Glu8413Lys variant is uncertain at this time. References: Zhang Q et al. Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. Hum Mol Genet. 2007 Dec 1;16(23):2816-33. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 29, 2023	Variant summary: SYNE1 c.25237G>A (p.Glu8413Lys) results in a conservative amino acid change located in a spectrin repeat (IPR002017) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00067 in 251482 control chromosomes, predominantly at a frequency of 0.0017 within the Latino subpopulation in the gnomAD database. This relatively high frequency suggests that the variant is likely not associated with a high penetrance, early onset dominant disease phenotype. The variant c.25237G>A has been reported in the literature in individuals affected with phenotypes suggestive of muscular disease (e.g. Zhang_2007, Kuhn_2016, Cerino_2021, Nallamilli_2018), however without strong evidence of causality (i.e. lack cosegregation evidence, atypical phenotype, or presence of other variants was noted in some of these cases). At least one of these publications reports experimental evidence evaluating an impact on protein function, however these results showed no damaging effect of this variant (Zhang_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17761684, 32934002, 32934002, 30564623). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 09, 2021	- -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2020	This variant is associated with the following publications: (PMID: 17761684) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	SYNE1: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 08, 2018	- -

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2007	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Autosomal recessive ataxia, Beauce type Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 8413 of the SYNE1 protein (p.Glu8413Lys). This variant is present in population databases (rs119103248, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Emery–Dreifuss muscular dystrophy (PMID: 17761684). ClinVar contains an entry for this variant (Variation ID: 2334). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect SYNE1 function (PMID: 17761684). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.;T;T;T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D;T;T;D;D;D;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.020	T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.1	N;.;N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.16	T;.;T;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T;T;T
Polyphen		0.61	P;.;.;.;.;.;.
Vest4		0.46
MVP		0.60
MPC		0.15
ClinPred		0.032	T
GERP RS		5.9
Varity_R		0.38
gMVP		0.21

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs119103248; hg19: chr6-152461162; COSMIC: COSV104542096;