6-152308482-C-T

Position:

• chr6-152308482-C-T

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.17346+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,613,560 control chromosomes in the GnomAD database, including 85,973 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6749 hom., cov: 31)
  • Exomes 𝑓: 0.32 (79224 hom.)
• Consequence: SYNE1 NM_182961.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003899
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.307

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 6-152308482-C-T is Benign according to our data. Variant chr6-152308482-C-T is described in ClinVar as [Benign]. Clinvar id is 130412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152308482-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.17346+7G>A		splice_region_variant, intron_variant		ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.17346+7G>A		splice_region_variant, intron_variant		1	NM_182961.4	P1
SYNE1	ENST00000423061.6	c.17133+7G>A		splice_region_variant, intron_variant		1
SYNE1	ENST00000367256.9	n.1038+7G>A		splice_region_variant, intron_variant, non_coding_transcript_variant		1
SYNE1	ENST00000409694.6	n.930+7G>A		splice_region_variant, intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41186 AN: 151902 Hom.: 6748 Cov.: 31

Gnomad AFR AF: 0.0907

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.289

GnomAD3 exomes AF: 0.332 AC: 83373 AN: 251378 Hom.: 15045 AF XY: 0.333 AC XY: 45264 AN XY: 135870

Gnomad AFR exome AF: 0.0837

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.367

Gnomad EAS exome AF: 0.585

Gnomad SAS exome AF: 0.328

Gnomad FIN exome AF: 0.360

Gnomad NFE exome AF: 0.321

Gnomad OTH exome AF: 0.325

GnomAD4 exome AF: 0.323 AC: 472043 AN: 1461542 Hom.: 79224 Cov.: 53 AF XY: 0.324 AC XY: 235837 AN XY: 727078

Gnomad4 AFR exome AF: 0.0785

Gnomad4 AMR exome AF: 0.315

Gnomad4 ASJ exome AF: 0.367

Gnomad4 EAS exome AF: 0.578

Gnomad4 SAS exome AF: 0.329

Gnomad4 FIN exome AF: 0.354

Gnomad4 NFE exome AF: 0.319

Gnomad4 OTH exome AF: 0.325

GnomAD4 genome AF: 0.271 AC: 41193 AN: 152018 Hom.: 6749 Cov.: 31 AF XY: 0.276 AC XY: 20503 AN XY: 74282

Gnomad4 AFR AF: 0.0905

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.373

Gnomad4 EAS AF: 0.592

Gnomad4 SAS AF: 0.351

Gnomad4 FIN AF: 0.351

Gnomad4 NFE AF: 0.326

Gnomad4 OTH AF: 0.290

Alfa AF: 0.308 Hom.: 13482

Bravo AF: 0.257

Asia WGS AF: 0.429 AC: 1495 AN: 3478

EpiCase AF: 0.316

EpiControl AF: 0.314

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal recessive ataxia, Beauce type Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 02, 2018

- -

Arthrogryposis multiplex congenita 3, myogenic type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.47
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs9383985; hg19: chr6-152629617; COSMIC: COSV54931037;