6-152325144-G-C

Variant names:

• chr6-152325144-G-C
• rs9383987
• NM_182961.4:c.15597C>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182961.4(SYNE1):​c.15597C>G​(p.Ala5199Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0365 in 1,614,070 control chromosomes in the GnomAD database, including 1,546 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (174 hom., cov: 33)
  • Exomes 𝑓: 0.036 (1372 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0140

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 6-152325144-G-C is Benign according to our data. Variant chr6-152325144-G-C is described in ClinVar as [Benign]. Clinvar id is 130409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152325144-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.014 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.15597C>G	p.Ala5199Ala	synonymous_variant	Exon 81 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.15597C>G	p.Ala5199Ala	synonymous_variant	Exon 81 of 146	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6	c.15384C>G	p.Ala5128Ala	synonymous_variant	Exon 80 of 146	1		ENSP00000396024.1
SYNE1	ENST00000490135.6	n.2943C>G		non_coding_transcript_exon_variant	Exon 5 of 11	1

Frequencies

GnomAD3 genomes AF: 0.0412 AC: 6271 AN: 152064 Hom.: 174 Cov.: 33

Gnomad AFR AF: 0.0515

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0339

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.0369

Gnomad FIN AF: 0.0323

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0320

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0450 AC: 11327 AN: 251436 Hom.: 437 AF XY: 0.0432 AC XY: 5867 AN XY: 135898

Gnomad AFR exome AF: 0.0489

Gnomad AMR exome AF: 0.0516

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.162

Gnomad SAS exome AF: 0.0362

Gnomad FIN exome AF: 0.0358

Gnomad NFE exome AF: 0.0307

Gnomad OTH exome AF: 0.0376

GnomAD4 exome AF: 0.0360 AC: 52600 AN: 1461888 Hom.: 1372 Cov.: 32 AF XY: 0.0356 AC XY: 25881 AN XY: 727246

Gnomad4 AFR exome AF: 0.0513

Gnomad4 AMR exome AF: 0.0521

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.152

Gnomad4 SAS exome AF: 0.0344

Gnomad4 FIN exome AF: 0.0370

Gnomad4 NFE exome AF: 0.0311

Gnomad4 OTH exome AF: 0.0395

GnomAD4 genome AF: 0.0413 AC: 6280 AN: 152182 Hom.: 174 Cov.: 33 AF XY: 0.0417 AC XY: 3101 AN XY: 74408

Gnomad4 AFR AF: 0.0517

Gnomad4 AMR AF: 0.0339

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.0365

Gnomad4 FIN AF: 0.0323

Gnomad4 NFE AF: 0.0320

Gnomad4 OTH AF: 0.0379

Alfa AF: 0.0302 Hom.: 27

Bravo AF: 0.0427

Asia WGS AF: 0.0840 AC: 293 AN: 3478

EpiCase AF: 0.0298

EpiControl AF: 0.0283

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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. -

-

Clinical Genetics, Academic Medical Center

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

- -

Jan 28, 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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Autosomal recessive ataxia, Beauce type Benign:1

Jan 12, 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 12, 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	-0.50
CADD	Benign	6.1
DANN	Benign	0.77

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9383987; hg19: chr6-152646279; COSMIC: COSV55011867;