6-152354719-A-G

Position:

• chr6-152354719-A-G

Variant summary

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

The NM_033071.5(SYNE1):​c.10881+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 1,613,882 control chromosomes in the GnomAD database, including 292,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (25511 hom., cov: 33)
  • Exomes 𝑓: 0.60 (267013 hom.)
• Consequence: SYNE1 NM_033071.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.151

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]

SYNE1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-152354719-A-G is Benign according to our data. Variant chr6-152354719-A-G is described in ClinVar as [Benign]. Clinvar id is 130393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152354719-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.10866T>C	p.Ser3622Ser	synonymous_variant	67/146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.10866T>C	p.Ser3622Ser	synonymous_variant	67/146	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6	c.10881+6T>C		splice_region_variant, intron_variant		1		ENSP00000396024.1
SYNE1	ENST00000471834.1	n.4004T>C		non_coding_transcript_exon_variant	10/19	1

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87800 AN: 151904 Hom.: 25491 Cov.: 33

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.592

GnomAD3 exomes AF: 0.586 AC: 147282 AN: 251462 Hom.: 43531 AF XY: 0.584 AC XY: 79338 AN XY: 135902

Gnomad AFR exome AF: 0.514

Gnomad AMR exome AF: 0.603

Gnomad ASJ exome AF: 0.647

Gnomad EAS exome AF: 0.609

Gnomad SAS exome AF: 0.526

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.605

Gnomad OTH exome AF: 0.588

GnomAD4 exome AF: 0.603 AC: 881791 AN: 1461860 Hom.: 267013 Cov.: 70 AF XY: 0.601 AC XY: 436836 AN XY: 727234

Gnomad4 AFR exome AF: 0.507

Gnomad4 AMR exome AF: 0.604

Gnomad4 ASJ exome AF: 0.648

Gnomad4 EAS exome AF: 0.641

Gnomad4 SAS exome AF: 0.525

Gnomad4 FIN exome AF: 0.546

Gnomad4 NFE exome AF: 0.613

Gnomad4 OTH exome AF: 0.597

GnomAD4 genome AF: 0.578 AC: 87867 AN: 152022 Hom.: 25511 Cov.: 33 AF XY: 0.574 AC XY: 42667 AN XY: 74328

Gnomad4 AFR AF: 0.520

Gnomad4 AMR AF: 0.613

Gnomad4 ASJ AF: 0.641

Gnomad4 EAS AF: 0.624

Gnomad4 SAS AF: 0.535

Gnomad4 FIN AF: 0.533

Gnomad4 NFE AF: 0.609

Gnomad4 OTH AF: 0.594

Alfa AF: 0.600 Hom.: 17139

Bravo AF: 0.582

Asia WGS AF: 0.597 AC: 2078 AN: 3478

EpiCase AF: 0.598

EpiControl AF: 0.594

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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive ataxia, Beauce type 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 12, 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. -

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 12, 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

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.85
CADD	Benign	0.56
DANN	Benign	0.37

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9397102; hg19: chr6-152675854; COSMIC: COSV54935173;