rs71575926

Variant names:

• chr6-152339316-G-A
• rs71575926
• NM_182961.4:c.12276C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182961.4(SYNE1):​c.12276C>T​(p.Leu4092Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,613,840 control chromosomes in the GnomAD database, including 14,862 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1300 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13562 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0800
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 6-152339316-G-A is Benign according to our data. Variant chr6-152339316-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.12276C>T	p.Leu4092Leu	synonymous_variant	Exon 75 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.12276C>T	p.Leu4092Leu	synonymous_variant	Exon 75 of 146	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6	c.12063C>T	p.Leu4021Leu	synonymous_variant	Exon 74 of 146	1		ENSP00000396024.1
SYNE1	ENST00000471834.1	n.5414C>T		non_coding_transcript_exon_variant	Exon 18 of 19	1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18195 AN: 152152 Hom.: 1300 Cov.: 33

Gnomad AFR AF: 0.0886

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.0790

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.0321

Gnomad SAS AF: 0.0385

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.0884

GnomAD2 exomes AF: 0.113 AC: 28415 AN: 251412 AF XY: 0.112

Gnomad AFR exome AF: 0.0891

Gnomad AMR exome AF: 0.0558

Gnomad ASJ exome AF: 0.0470

Gnomad EAS exome AF: 0.0306

Gnomad FIN exome AF: 0.257

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.129 AC: 188074 AN: 1461570 Hom.: 13562 Cov.: 33 AF XY: 0.126 AC XY: 91925 AN XY: 727108

African (AFR) AF: 0.0932 AC: 3121 AN: 33476

American (AMR) AF: 0.0584 AC: 2612 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0454 AC: 1186 AN: 26120

East Asian (EAS) AF: 0.0258 AC: 1023 AN: 39676

South Asian (SAS) AF: 0.0456 AC: 3933 AN: 86246

European-Finnish (FIN) AF: 0.252 AC: 13463 AN: 53392

Middle Eastern (MID) AF: 0.0788 AC: 454 AN: 5764

European-Non Finnish (NFE) AF: 0.140 AC: 155321 AN: 1111802

Other (OTH) AF: 0.115 AC: 6961 AN: 60378

GnomAD4 genome AF: 0.120 AC: 18204 AN: 152270 Hom.: 1300 Cov.: 33 AF XY: 0.124 AC XY: 9235 AN XY: 74446

African (AFR) AF: 0.0886 AC: 3682 AN: 41570

American (AMR) AF: 0.0787 AC: 1204 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 142 AN: 3468

East Asian (EAS) AF: 0.0324 AC: 168 AN: 5188

South Asian (SAS) AF: 0.0389 AC: 188 AN: 4828

European-Finnish (FIN) AF: 0.272 AC: 2879 AN: 10590

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9520 AN: 68018

Other (OTH) AF: 0.0875 AC: 185 AN: 2114

Alfa AF: 0.125 Hom.: 673

Bravo AF: 0.106

Asia WGS AF: 0.0400 AC: 141 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.138

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 05, 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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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. -

not provided Benign:2

Nov 02, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

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
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.1
DANN	Benign	0.77
PhyloP100		0.080
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs71575926; hg19: chr6-152660451;