rs9397509

chr6-152463486-T-C

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.1964A>G(p.Gln655Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00714 in 1,613,582 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (57 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 7.88

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=0.0076130033).
• BP6: Variant 6-152463486-T-C is Benign according to our data. Variant chr6-152463486-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 130417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152463486-T-C is described in Lovd as [Likely_pathogenic]. Variant chr6-152463486-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 905 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.1964A>G	p.Gln655Arg	missense_variant	19/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.1964A>G	p.Gln655Arg	missense_variant	19/146	1	NM_182961.4	P1

Frequencies

GnomAD3 genomes AF: 0.00595 AC: 905 AN: 152162 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00791

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00627 AC: 1573 AN: 250734 Hom.: 9 AF XY: 0.00603 AC XY: 817 AN XY: 135508

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.00487

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.00786

Gnomad OTH exome AF: 0.00687

GnomAD4 exome AF: 0.00726 AC: 10611 AN: 1461302 Hom.: 57 Cov.: 32 AF XY: 0.00711 AC XY: 5171 AN XY: 726932

Gnomad4 AFR exome AF: 0.000867

Gnomad4 AMR exome AF: 0.00488

Gnomad4 ASJ exome AF: 0.0161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0126

Gnomad4 NFE exome AF: 0.00792

Gnomad4 OTH exome AF: 0.00756

GnomAD4 genome AF: 0.00594 AC: 904 AN: 152280 Hom.: 6 Cov.: 32 AF XY: 0.00565 AC XY: 421 AN XY: 74458

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00654

Gnomad4 ASJ AF: 0.0208

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.00789

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00825 Hom.: 17

Bravo AF: 0.00557

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00619 AC: 752

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00796

EpiControl AF: 0.00700

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 19, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SYNE1: BP4, BS2 -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 24, 2014	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Autosomal recessive ataxia, Beauce type Benign:1

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. -

SYNE1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2019

This variant is classified as 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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;T;.;.;.;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0076	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.;.;M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.6	N;N;N;D;D;D;D;D
REVEL	Benign	0.14
Sift	Benign	0.42	T;D;T;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;D;.;D;P
Vest4		0.55
MVP		0.41
MPC		0.57
ClinPred		0.016	T
GERP RS		5.6
Varity_R		0.26
gMVP		0.40

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9397509; hg19: chr6-152784621;