rs116007471

chr6-152268070-G-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.18801C>T(p.Thr6267=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,613,744 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (12 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.155

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=-0.85).
• BP6: Variant 6-152268070-G-A is Benign according to our data. Variant chr6-152268070-G-A is described in ClinVar as [Benign]. Clinvar id is 130415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152268070-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.155 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00906 (1380/152252) while in subpopulation AFR AF= 0.0312 (1294/41528). AF 95% confidence interval is 0.0297. There are 22 homozygotes in gnomad4. There are 639 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1372 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.18801C>T	p.Thr6267=	synonymous_variant	100/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.18801C>T	p.Thr6267=	synonymous_variant	100/146	1	NM_182961.4	P1

Frequencies

GnomAD3 genomes AF: 0.00902 AC: 1372 AN: 152134 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00299 AC: 752 AN: 251238 Hom.: 10 AF XY: 0.00233 AC XY: 316 AN XY: 135782

Gnomad AFR exome AF: 0.0333

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00121 AC: 1770 AN: 1461492 Hom.: 12 Cov.: 31 AF XY: 0.00121 AC XY: 882 AN XY: 727072

Gnomad4 AFR exome AF: 0.0321

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00334

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000891

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00906 AC: 1380 AN: 152252 Hom.: 22 Cov.: 32 AF XY: 0.00858 AC XY: 639 AN XY: 74436

Gnomad4 AFR AF: 0.0312

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00436 Hom.: 6

Bravo AF: 0.0108

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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. -
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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Autosomal recessive ataxia, Beauce type Benign:1

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. -

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.74
Dann	Benign	0.53

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs116007471; hg19: chr6-152589205;