rs139170018

chr6-152326059-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_182961.4(SYNE1):c.15337G>A(p.Val5113Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000945 in 1,614,152 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00056 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00099 (0 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 5.01

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SYNE1
• BP4: Computational evidence support a benign effect (MetaRNN=0.038308978).
• BP6: Variant 6-152326059-C-T is Benign according to our data. Variant chr6-152326059-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198681.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=2, Benign=1}. Variant chr6-152326059-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.15337G>A	p.Val5113Ile	missense_variant	80/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.15337G>A	p.Val5113Ile	missense_variant	80/146	1	NM_182961.4	P1
SYNE1	ENST00000423061.6	c.15124G>A	p.Val5042Ile	missense_variant	79/146	1
SYNE1	ENST00000490135.6	n.2683G>A		non_coding_transcript_exon_variant	4/11	1

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000744 AC: 187 AN: 251262 Hom.: 0 AF XY: 0.000832 AC XY: 113 AN XY: 135836

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000986 AC: 1441 AN: 1461862 Hom.: 0 Cov.: 33 AF XY: 0.00103 AC XY: 751 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48 AN XY: 74460

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000744 Hom.: 0

Bravo AF: 0.000672

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000766 AC: 93

EpiCase AF: 0.00104

EpiControl AF: 0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2023	Reported in the heterozygous state in a patient with hypertrophic cardiomyopathy in published literature (Forleo et al., 2017); additional information was not provided; Reported in the heterozygous state in an individual tested as part of a sudden infant death syndrome cohort in published literature (Neubauer et al., 2017); additional information was not provided; Reported in an individual with cerebellar syndrome and CPEO in the published literature (Plutino et al., 2018); a second variant in SYNE1 was also identified but is classified as likely benign; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28750076, 28074886, 29625556) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 25, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SYNE1: BP4 -

Autosomal recessive ataxia, Beauce type Uncertain:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jul 23, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 27, 2014

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 5042 of the SYNE1 protein (p.Val5042Ile). This variant is present in population databases (rs139170018, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and sudden infant death syndrome (PMID: 28074886, 28750076). ClinVar contains an entry for this variant (Variation ID: 198681). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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. -

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	0.095
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.038	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.11	N;N
REVEL	Benign	0.14
Sift	Benign	0.54	T;T
Sift4G	Uncertain	0.034	D;D
Polyphen		0.97	D;.
Vest4		0.33
MVP		0.43
MPC		0.11
ClinPred		0.039	T
GERP RS		5.2
Varity_R		0.051
gMVP		0.11

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs139170018; hg19: chr6-152647194; COSMIC: COSV104541904;