rs143639400

chr6-152230593-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.21149G>A(p.Arg7050Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2
• Conservation: PhyloP100: 0.0380

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=0.015934825).
• BP6: Variant 6-152230593-C-T is Benign according to our data. Variant chr6-152230593-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287711.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=1, Benign=1}. Variant chr6-152230593-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.21149G>A	p.Arg7050Gln	missense_variant	115/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.21149G>A	p.Arg7050Gln	missense_variant	115/146	1	NM_182961.4	P1
SYNE1	ENST00000423061.6	c.20936G>A	p.Arg6979Gln	missense_variant	114/146	1
SYNE1	ENST00000367256.9	n.4841G>A		non_coding_transcript_exon_variant	30/61	1
SYNE1	ENST00000409694.6	n.4733G>A		non_coding_transcript_exon_variant	28/59	1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000235 AC: 59 AN: 251354 Hom.: 0 AF XY: 0.000236 AC XY: 32 AN XY: 135858

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000285 AC: 417 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.000264 AC XY: 192 AN XY: 727204

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000326

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74450

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000357 Hom.: 0

Bravo AF: 0.000502

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000255 AC: 31

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 04, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 23, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 08, 2024

Variant summary: SYNE1 c.20936G>A (p.Arg6979Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 251354 control chromosomes. To our knowledge, no occurrence of c.20936G>A in individuals affected with SYNE1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 287711. VUS, n=7; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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 03, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 6979 of the SYNE1 protein (p.Arg6979Gln). This variant is present in population databases (rs143639400, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 287711). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Autosomal recessive ataxia, Beauce type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	0.064
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	3.9
Dann	Benign	0.97
DEOGEN2	Benign	0.21	T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.077	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-2.1	N;.;N
REVEL	Benign	0.026
Sift	Benign	0.038	D;.;D
Sift4G	Uncertain	0.059	T;T;T
Polyphen		0.28	B;.;.
Vest4		0.13
MVP		0.12
MPC		0.15
ClinPred		0.022	T
GERP RS		-3.7
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: rs143639400; hg19: chr6-152551728; COSMIC: COSV55099821; COSMIC: COSV55099821;