rs6908392

Positions:

• chr6-152352012-G-A
• chr6-152352012-G-C

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.11580+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,611,640 control chromosomes in the GnomAD database, including 291,700 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25249 hom., cov: 32)
  • Exomes 𝑓: 0.60 (266451 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.117

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=-0.82).
• BP6: Variant 6-152352012-G-A is Benign according to our data. Variant chr6-152352012-G-A is described in ClinVar as [Benign]. Clinvar id is 262154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152352012-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.11580+15C>T		intron_variant		ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.11580+15C>T		intron_variant		1	NM_182961.4	ENSP00000356224	P1
SYNE1	ENST00000423061.6	c.11535+15C>T		intron_variant		1		ENSP00000396024
SYNE1	ENST00000471834.1	n.4718+15C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87282 AN: 151886 Hom.: 25231 Cov.: 32

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.621

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.589

GnomAD3 exomes AF: 0.584 AC: 144990 AN: 248276 Hom.: 42673 AF XY: 0.582 AC XY: 78287 AN XY: 134430

Gnomad AFR exome AF: 0.503

Gnomad AMR exome AF: 0.602

Gnomad ASJ exome AF: 0.647

Gnomad EAS exome AF: 0.605

Gnomad SAS exome AF: 0.526

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.604

Gnomad OTH exome AF: 0.588

GnomAD4 exome AF: 0.603 AC: 880097 AN: 1459634 Hom.: 266451 Cov.: 35 AF XY: 0.600 AC XY: 436084 AN XY: 726236

Gnomad4 AFR exome AF: 0.494

Gnomad4 AMR exome AF: 0.604

Gnomad4 ASJ exome AF: 0.648

Gnomad4 EAS exome AF: 0.640

Gnomad4 SAS exome AF: 0.525

Gnomad4 FIN exome AF: 0.546

Gnomad4 NFE exome AF: 0.613

Gnomad4 OTH exome AF: 0.595

GnomAD4 genome AF: 0.575 AC: 87345 AN: 152006 Hom.: 25249 Cov.: 32 AF XY: 0.571 AC XY: 42388 AN XY: 74278

Gnomad4 AFR AF: 0.508

Gnomad4 AMR AF: 0.612

Gnomad4 ASJ AF: 0.641

Gnomad4 EAS AF: 0.620

Gnomad4 SAS AF: 0.535

Gnomad4 FIN AF: 0.534

Gnomad4 NFE AF: 0.609

Gnomad4 OTH AF: 0.591

Alfa AF: 0.606 Hom.: 48561

Bravo AF: 0.578

Asia WGS AF: 0.594 AC: 2067 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 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. -

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	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	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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	-0.82
CADD	Benign	1.3
DANN	Benign	0.20

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6908392; hg19: chr6-152673147; COSMIC: COSV54935163;