rs9478314

Variant names:

• chr6-152331902-T-C
• rs9478314
• NM_182961.4:c.12795-12A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182961.4(SYNE1):​c.12795-12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,608,436 control chromosomes in the GnomAD database, including 172,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18122 hom., cov: 33)
  • Exomes 𝑓: 0.45 (154276 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Scores: Splicing: ADA: 0.00005298
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0950

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-152331902-T-C is Benign according to our data. Variant chr6-152331902-T-C is described in ClinVar as [Benign]. Clinvar id is 262160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152331902-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.12795-12A>G		intron_variant	Intron 77 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.12795-12A>G		intron_variant	Intron 77 of 145	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6	c.12582-12A>G		intron_variant	Intron 76 of 145	1		ENSP00000396024.1
SYNE1	ENST00000490135.6	n.141-12A>G		intron_variant	Intron 1 of 10	1

Frequencies

GnomAD3 genomes AF: 0.481 AC: 73070 AN: 152010 Hom.: 18103 Cov.: 33

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.477

GnomAD3 exomes AF: 0.468 AC: 115505 AN: 246858 Hom.: 29095 AF XY: 0.458 AC XY: 61500 AN XY: 134324

Gnomad AFR exome AF: 0.540

Gnomad AMR exome AF: 0.673

Gnomad ASJ exome AF: 0.549

Gnomad EAS exome AF: 0.158

Gnomad SAS exome AF: 0.389

Gnomad FIN exome AF: 0.458

Gnomad NFE exome AF: 0.462

Gnomad OTH exome AF: 0.468

GnomAD4 exome AF: 0.455 AC: 662596 AN: 1456308 Hom.: 154276 Cov.: 51 AF XY: 0.453 AC XY: 328383 AN XY: 724826

Gnomad4 AFR exome AF: 0.529

Gnomad4 AMR exome AF: 0.661

Gnomad4 ASJ exome AF: 0.555

Gnomad4 EAS exome AF: 0.200

Gnomad4 SAS exome AF: 0.399

Gnomad4 FIN exome AF: 0.455

Gnomad4 NFE exome AF: 0.456

Gnomad4 OTH exome AF: 0.445

GnomAD4 genome AF: 0.481 AC: 73128 AN: 152128 Hom.: 18122 Cov.: 33 AF XY: 0.478 AC XY: 35566 AN XY: 74374

Gnomad4 AFR AF: 0.540

Gnomad4 AMR AF: 0.585

Gnomad4 ASJ AF: 0.550

Gnomad4 EAS AF: 0.157

Gnomad4 SAS AF: 0.373

Gnomad4 FIN AF: 0.444

Gnomad4 NFE AF: 0.458

Gnomad4 OTH AF: 0.480

Alfa AF: 0.490 Hom.: 5681

Bravo AF: 0.493

Asia WGS AF: 0.304 AC: 1061 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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. -

Autosomal recessive ataxia, Beauce type Benign:2

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. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:2

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. -

Jul 15, 2021

Genome-Nilou Lab

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

- -

Arthrogryposis multiplex congenita 3, myogenic type Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.43
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000053
dbscSNV1_RF	Benign	0.0020

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

Publications

LitVar

Other links and lift over

dbSNP: rs9478314; hg19: chr6-152653037; COSMIC: COSV54902523; COSMIC: COSV54902523;