6-152376540-G-T

Position:

• chr6-152376540-G-T

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.9165C>A​(p.Ser3055=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,613,918 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (13 hom., cov: 32)
  • Exomes 𝑓: 0.013 (180 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.29

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=-0.48).
• BP6: Variant 6-152376540-G-T is Benign according to our data. Variant chr6-152376540-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 262203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152376540-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00867 (1320/152204) while in subpopulation SAS AF= 0.0266 (128/4816). AF 95% confidence interval is 0.0228. There are 13 homozygotes in gnomad4. There are 655 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1320 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.9165C>A	p.Ser3055=	synonymous_variant	58/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.9165C>A	p.Ser3055=	synonymous_variant	58/146	1	NM_182961.4	P1

Frequencies

GnomAD3 genomes AF: 0.00867 AC: 1319 AN: 152086 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.0122 AC: 3075 AN: 251136 Hom.: 39 AF XY: 0.0138 AC XY: 1876 AN XY: 135788

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00431

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0311

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.00997

GnomAD4 exome AF: 0.0133 AC: 19489 AN: 1461714 Hom.: 180 Cov.: 30 AF XY: 0.0138 AC XY: 10064 AN XY: 727166

Gnomad4 AFR exome AF: 0.00218

Gnomad4 AMR exome AF: 0.00425

Gnomad4 ASJ exome AF: 0.00964

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0318

Gnomad4 FIN exome AF: 0.0134

Gnomad4 NFE exome AF: 0.0132

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.00867 AC: 1320 AN: 152204 Hom.: 13 Cov.: 32 AF XY: 0.00880 AC XY: 655 AN XY: 74400

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0266

Gnomad4 FIN AF: 0.0114

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00994 Hom.: 9

Bravo AF: 0.00736

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0128

EpiControl AF: 0.0138

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 27, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Jan 31, 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. -

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	-0.48
CADD	Benign	7.3
DANN	Benign	0.77

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs117020413; hg19: chr6-152697675;