6-152358459-A-G

Variant names:

• chr6-152358459-A-G
• rs62426382
• NM_182961.4:c.10522T>C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_182961.4(SYNE1):​c.10522T>C​(p.Leu3508Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,614,024 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (16 hom., cov: 32)
  • Exomes 𝑓: 0.014 (173 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.53

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 6-152358459-A-G is Benign according to our data. Variant chr6-152358459-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 130390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152358459-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0141 (20623/1461868) while in subpopulation NFE AF= 0.0156 (17343/1111996). AF 95% confidence interval is 0.0154. There are 173 homozygotes in gnomad4_exome. There are 10003 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1603 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.10522T>C	p.Leu3508Leu	synonymous_variant	Exon 66 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.10522T>C	p.Leu3508Leu	synonymous_variant	Exon 66 of 146	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6	c.10543T>C	p.Leu3515Leu	synonymous_variant	Exon 66 of 146	1		ENSP00000396024.1
SYNE1	ENST00000471834.1	n.3660T>C		non_coding_transcript_exon_variant	Exon 9 of 19	1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1604 AN: 152038 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0110 AC: 2761 AN: 251480 Hom.: 14 AF XY: 0.0113 AC XY: 1535 AN XY: 135912

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00792

Gnomad ASJ exome AF: 0.0413

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0141 AC: 20623 AN: 1461868 Hom.: 173 Cov.: 31 AF XY: 0.0138 AC XY: 10003 AN XY: 727236

Gnomad4 AFR exome AF: 0.00209

Gnomad4 AMR exome AF: 0.00856

Gnomad4 ASJ exome AF: 0.0396

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00219

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.0105 AC: 1603 AN: 152156 Hom.: 16 Cov.: 32 AF XY: 0.0101 AC XY: 749 AN XY: 74368

Gnomad4 AFR AF: 0.00272

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.0386

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0102

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0144 Hom.: 8

Bravo AF: 0.0111

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0138

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jan 08, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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

- -

not provided Benign:2

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SYNE1: BP4, BP7, BS1, BS2 -

-

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. -

SYNE1-related disorder Benign:1

May 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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	-0.34
CADD	Benign	2.7
DANN	Benign	0.73

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs62426382; hg19: chr6-152679594;