rs138787771

chr6-152180281-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_182961.4(SYNE1):c.23315G>A(p.Arg7772Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00624 in 1,613,974 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7772W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0041 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0065 (48 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: 2.55

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SYNE1
• BP4: Computational evidence support a benign effect (MetaRNN=0.00968194).
• BP6: Variant 6-152180281-C-T is Benign according to our data. Variant chr6-152180281-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 194147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152180281-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 630 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.23315G>A	p.Arg7772Gln	missense_variant	129/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.23315G>A	p.Arg7772Gln	missense_variant	129/146	1	NM_182961.4	P1

Frequencies

GnomAD3 genomes AF: 0.00414 AC: 630 AN: 152104 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00692

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00351 AC: 881 AN: 250934 Hom.: 1 AF XY: 0.00363 AC XY: 492 AN XY: 135604

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00641

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00645 AC: 9435 AN: 1461752 Hom.: 48 Cov.: 32 AF XY: 0.00623 AC XY: 4529 AN XY: 727178

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.00157

Gnomad4 NFE exome AF: 0.00794

Gnomad4 OTH exome AF: 0.00503

GnomAD4 genome AF: 0.00415 AC: 631 AN: 152222 Hom.: 1 Cov.: 31 AF XY: 0.00372 AC XY: 277 AN XY: 74414

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000944

Gnomad4 NFE AF: 0.00693

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00615 Hom.: 5

Bravo AF: 0.00428

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00371 AC: 450

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2020	This variant is associated with the following publications: (PMID: 31692161, 32075053) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SYNE1: BP4, BS2 -

not specified Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 24, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg7701Gln (aka R7701Q, c.23102 G>A) in SYNE1 (using NM_033071.3). The variant is novel. It is a non-conservative amino acid change with a positively charged arginine being changed to a neutral, polar glutamine. The arginine at codon 7701 is not conserved across species. In silico analysis predicts a benign effect on protein structure and function (per lab report). SYNE1 encodes nesprin 1 (nuclear envelope spectrin repeat 1). Nesprin 1 and 2 are associated with the nuclear membrane and bind lamin A and emerin. These genes are highly expressed in both heart and skeletal muscle. It has been suggested that variants in SYNE1 may contribute to Emery-Dreiffus muscular dystrophy (EDMD). Using a candidate gene approach, Zang et al (2011), sequenced SYNE1 and SYNE2 (encoding nesprin 2) in 190 patients with EDMD and EDMD-like phenotypes who did not have causative variants in LMNA or EMD. This identified three patients who carried an SYNE1 missense variant that was not present in 192 control individuals. One of these patients was a compound heterozygote for a missense variant in SYNE2. Only minimal segregation analysis could be performed. The patient who was a compound heterozygote had an affected mother, who carried the SYNE2 variant and a seemingly unaffected father, who carried the SYNE1 variant. Dr. Beth McNally’s group reported on a patient with dilated cardiomyopathy requiring heart transplant who had a missense variant in SYNE1 (p.Arg374His) (Puckelwartz et al 2010). They found that mice lacking the carboxy-terminus of nesprin-1develop cardiomyopathy with conduction system disease. SYNE1 has also been linked to autosomal recessive spinocerebellar ataxia 8. Nesprin-1 is over 8700 amino acids long. p.Arg7701Gln was observed in 47 of 8600 alleles from European Americans in the NHLBI ESP, which presumably indicated 47 of 4300 individuals were heterozygous for the variant. 12 of 4406 African American alleles (likely 6 of 2203 individuals) (as of April 23rd, 2013). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2015	- -

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 19, 2024

- -

Autosomal recessive ataxia, Beauce type Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

SYNE1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2019

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	Benign	0.070
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;T;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.0097	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.4	N;.;D;N;D
REVEL	Benign	0.13
Sift	Uncertain	0.027	D;.;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		0.96	P;.;.;.;.
Vest4		0.22
MVP		0.43
MPC		0.16
ClinPred		0.045	T
GERP RS		3.3
Varity_R		0.14
gMVP		0.28

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs138787771; hg19: chr6-152501416;