rs34905593

chr6-152233922-T-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_182961.4(SYNE1):c.20571A>T(p.Ser6857=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,614,078 control chromosomes in the GnomAD database, including 461 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (35 hom., cov: 32)
  • Exomes 𝑓: 0.022 (426 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.658

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 6-152233922-T-A is Benign according to our data. Variant chr6-152233922-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 130418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152233922-T-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.658 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0171 (2598/152274) while in subpopulation NFE AF= 0.025 (1702/68012). AF 95% confidence interval is 0.024. There are 35 homozygotes in gnomad4. There are 1314 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2599 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.20571A>T	p.Ser6857=	synonymous_variant	112/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.20571A>T	p.Ser6857=	synonymous_variant	112/146	1	NM_182961.4	P1
SYNE1	ENST00000423061.6	c.20358A>T	p.Ser6786=	synonymous_variant	111/146	1
SYNE1	ENST00000367256.9	n.4263A>T		non_coding_transcript_exon_variant	27/61	1
SYNE1	ENST00000409694.6	n.4155A>T		non_coding_transcript_exon_variant	25/59	1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2599 AN: 152156 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.0196 AC: 4935 AN: 251310 Hom.: 65 AF XY: 0.0211 AC XY: 2863 AN XY: 135816

Gnomad AFR exome AF: 0.00381

Gnomad AMR exome AF: 0.00864

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0242

Gnomad FIN exome AF: 0.0323

Gnomad NFE exome AF: 0.0248

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0223 AC: 32628 AN: 1461804 Hom.: 426 Cov.: 31 AF XY: 0.0225 AC XY: 16375 AN XY: 727210

Gnomad4 AFR exome AF: 0.00367

Gnomad4 AMR exome AF: 0.00843

Gnomad4 ASJ exome AF: 0.0172

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0257

Gnomad4 FIN exome AF: 0.0341

Gnomad4 NFE exome AF: 0.0236

Gnomad4 OTH exome AF: 0.0197

GnomAD4 genome AF: 0.0171 AC: 2598 AN: 152274 Hom.: 35 Cov.: 32 AF XY: 0.0176 AC XY: 1314 AN XY: 74466

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0238

Gnomad4 FIN AF: 0.0300

Gnomad4 NFE AF: 0.0250

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0217 Hom.: 11

Bravo AF: 0.0143

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 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, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Genetic Services Laboratory, University of Chicago	Aug 23, 2013	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Autosomal recessive ataxia, Beauce type 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. -

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant;C5193121:Arthrogryposis multiplex congenita 3, myogenic type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

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	-0.54
Cadd	Benign	0.12
Dann	Benign	0.66

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34905593; hg19: chr6-152555057;