6-152347137-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_182961.4(SYNE1):c.12000G>A(p.Ala4000=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00639 in 1,614,152 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (52 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.60

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-152347137-C-T is Benign according to our data. Variant chr6-152347137-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 198654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152347137-C-T is described in Lovd as [Benign]. Variant chr6-152347137-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.
• BS2: High AC in GnomAd at 814 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.12000G>A	p.Ala4000=	synonymous_variant	73/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.12000G>A	p.Ala4000=	synonymous_variant	73/146	1	NM_182961.4	P1
SYNE1	ENST00000423061.6	c.11787G>A	p.Ala3929=	synonymous_variant	72/146	1
SYNE1	ENST00000471834.1	n.5138G>A		non_coding_transcript_exon_variant	16/19	1

Frequencies

GnomAD3 genomes AF: 0.00535 AC: 814 AN: 152148 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00737

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00565 AC: 1421 AN: 251470 Hom.: 5 AF XY: 0.00572 AC XY: 777 AN XY: 135908

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.00770

Gnomad OTH exome AF: 0.00651

GnomAD4 exome AF: 0.00649 AC: 9494 AN: 1461886 Hom.: 52 Cov.: 31 AF XY: 0.00639 AC XY: 4645 AN XY: 727246

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.0169

Gnomad4 NFE exome AF: 0.00711

Gnomad4 OTH exome AF: 0.00545

GnomAD4 genome AF: 0.00535 AC: 815 AN: 152266 Hom.: 2 Cov.: 32 AF XY: 0.00582 AC XY: 433 AN XY: 74454

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.00737

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00665 Hom.: 8

Bravo AF: 0.00453

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00812

EpiControl AF: 0.00711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 27, 2020	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SYNE1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 05, 2021	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Autosomal recessive ataxia, Beauce type Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.22
Dann	Benign	0.55

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs148493518; hg19: chr6-152668272; COSMIC: COSV55021916;