rs34610829

Variant names:

• chr6-152458798-G-A
• rs34610829
• NM_182961.4:c.2527C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-152458798-G-A
• chr6-152458798-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182961.4(SYNE1):​c.2527C>T​(p.Arg843Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0267 in 1,613,920 control chromosomes in the GnomAD database, including 681 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R843H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (46 hom., cov: 32)
  • Exomes 𝑓: 0.027 (635 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.32
• Publications: 18 publications found

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]

SYNE1 Gene-Disease associations (from GenCC):

• autosomal recessive ataxia, Beauce type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• arthrogryposis multiplex congenita 3, myogenic type

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive myogenic arthrogryposis multiplex congenita

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002840966).
• BP6: Variant 6-152458798-G-A is Benign according to our data. Variant chr6-152458798-G-A is described in ClinVar as [Benign]. Clinvar id is 130431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0218 (3317/152204) while in subpopulation NFE AF = 0.0331 (2250/67996). AF 95% confidence interval is 0.032. There are 46 homozygotes in GnomAd4. There are 1582 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.2527C>T	p.Arg843Cys	missense_variant	Exon 22 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.2527C>T	p.Arg843Cys	missense_variant	Exon 22 of 146	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3317 AN: 152086 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.00579

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0233

Gnomad FIN AF: 0.0212

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0331

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.0245 AC: 6165 AN: 251122 AF XY: 0.0256

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.0245

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.0341

Gnomad OTH exome AF: 0.0302

GnomAD4 exome AF: 0.0272 AC: 39729 AN: 1461716 Hom.: 635 Cov.: 32 AF XY: 0.0277 AC XY: 20146 AN XY: 727172

African (AFR) AF: 0.00493 AC: 165 AN: 33464

American (AMR) AF: 0.0184 AC: 823 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0246 AC: 642 AN: 26130

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39686

South Asian (SAS) AF: 0.0252 AC: 2170 AN: 86256

European-Finnish (FIN) AF: 0.0188 AC: 1002 AN: 53416

Middle Eastern (MID) AF: 0.0463 AC: 267 AN: 5764

European-Non Finnish (NFE) AF: 0.0298 AC: 33093 AN: 1111898

Other (OTH) AF: 0.0258 AC: 1561 AN: 60388

GnomAD4 genome AF: 0.0218 AC: 3317 AN: 152204 Hom.: 46 Cov.: 32 AF XY: 0.0213 AC XY: 1582 AN XY: 74414

African (AFR) AF: 0.00578 AC: 240 AN: 41538

American (AMR) AF: 0.0214 AC: 327 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0233 AC: 112 AN: 4812

European-Finnish (FIN) AF: 0.0212 AC: 225 AN: 10600

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0331 AC: 2250 AN: 67996

Other (OTH) AF: 0.0270 AC: 57 AN: 2112

Alfa AF: 0.0295 Hom.: 275

Bravo AF: 0.0206

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0291 AC: 112

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.0312 AC: 268

ExAC AF: 0.0251 AC: 3050

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Mar 08, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 18, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive ataxia, Beauce type Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.088
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.;T;.;.;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
MetaRNN	Benign	0.0028	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L;.;.;L;.;L;.
PhyloP100		4.3
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.8	D;.;D;N;N;N;D
REVEL	Benign	0.14
Sift	Uncertain	0.015	D;.;D;D;T;T;T
Sift4G	Uncertain	0.052	T;D;D;D;D;D;T
Polyphen		0.92	P;.;.;P;P;.;D
Vest4		0.21
MPC		0.32
ClinPred		0.014	T
GERP RS		5.3
PromoterAI		-0.039	Neutral
Varity_R		0.15
gMVP		0.084
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs34610829; hg19: chr6-152779933; COSMIC: COSV99037530; COSMIC: COSV99037530;