NM_182961.4:c.22473G>A

Variant names:

• chr6-152213633-C-T
• rs34891041
• NM_182961.4:c.22473G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_182961.4(SYNE1):​c.22473G>A​(p.Leu7491Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,613,978 control chromosomes in the GnomAD database, including 781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (91 hom., cov: 32)
  • Exomes 𝑓: 0.028 (690 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.417
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive ataxia, Beauce type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• arthrogryposis multiplex congenita 3, myogenic type

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive myogenic arthrogryposis multiplex congenita

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 6-152213633-C-T is Benign according to our data. Variant chr6-152213633-C-T is described in ClinVar as Benign. ClinVar VariationId is 130421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.417 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.031 (4722/152214) while in subpopulation AFR AF = 0.047 (1952/41538). AF 95% confidence interval is 0.0453. There are 91 homozygotes in GnomAd4. There are 2222 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 91 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.22473G>A	p.Leu7491Leu	synonymous_variant	Exon 123 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.22473G>A	p.Leu7491Leu	synonymous_variant	Exon 123 of 146	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.0310 AC: 4710 AN: 152096 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.0470

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0136

Gnomad EAS AF: 0.00927

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.0297

GnomAD2 exomes AF: 0.0241 AC: 6055 AN: 251424 AF XY: 0.0229

Gnomad AFR exome AF: 0.0471

Gnomad AMR exome AF: 0.00945

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.00701

Gnomad FIN exome AF: 0.0339

Gnomad NFE exome AF: 0.0318

Gnomad OTH exome AF: 0.0253

GnomAD4 exome AF: 0.0280 AC: 40858 AN: 1461764 Hom.: 690 Cov.: 33 AF XY: 0.0271 AC XY: 19715 AN XY: 727198

African (AFR) AF: 0.0482 AC: 1612 AN: 33474

American (AMR) AF: 0.0102 AC: 457 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 307 AN: 26130

East Asian (EAS) AF: 0.00824 AC: 327 AN: 39684

South Asian (SAS) AF: 0.00677 AC: 584 AN: 86254

European-Finnish (FIN) AF: 0.0351 AC: 1875 AN: 53420

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.0307 AC: 34113 AN: 1111920

Other (OTH) AF: 0.0258 AC: 1556 AN: 60392

GnomAD4 genome AF: 0.0310 AC: 4722 AN: 152214 Hom.: 91 Cov.: 32 AF XY: 0.0299 AC XY: 2222 AN XY: 74434

African (AFR) AF: 0.0470 AC: 1952 AN: 41538

American (AMR) AF: 0.0180 AC: 275 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 47 AN: 3468

East Asian (EAS) AF: 0.00929 AC: 48 AN: 5168

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4820

European-Finnish (FIN) AF: 0.0332 AC: 352 AN: 10590

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0287 AC: 1951 AN: 68018

Other (OTH) AF: 0.0322 AC: 68 AN: 2112

Alfa AF: 0.0308 Hom.: 150

Bravo AF: 0.0308

Asia WGS AF: 0.0290 AC: 100 AN: 3478

EpiCase AF: 0.0266

EpiControl AF: 0.0260

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Jan 28, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 18, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive ataxia, Beauce type Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.26
CADD	Benign	5.2
DANN	Benign	0.78
PhyloP100		0.42
Mutation Taster		=96/4	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs34891041; hg19: chr6-152534768;