NM_182961.4:c.11621A>C

Variant names:

• chr6-152350730-T-G
• rs13210127
• NM_182961.4:c.11621A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182961.4(SYNE1):​c.11621A>C​(p.Lys3874Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,614,084 control chromosomes in the GnomAD database, including 1,203 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (99 hom., cov: 32)
  • Exomes 𝑓: 0.026 (1104 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.447
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018830597).
• BP6: Variant 6-152350730-T-G is Benign according to our data. Variant chr6-152350730-T-G is described in ClinVar as Benign. ClinVar VariationId is 130394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182961.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.11621A>C	p.Lys3874Thr	missense	Exon 71 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.11576A>C	p.Lys3859Thr	missense	Exon 71 of 146	NP_149062.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.11621A>C	p.Lys3874Thr	missense	Exon 71 of 146	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.11576A>C	p.Lys3859Thr	missense	Exon 71 of 146	ENSP00000396024.1
	SYNE1	ENST00000471834.1	TSL:1	n.4759A>C		non_coding_transcript_exon	Exon 14 of 19

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3765 AN: 152102 Hom.: 97 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0429

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.0719

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.0366 AC: 9203 AN: 251310 AF XY: 0.0376

Gnomad AFR exome AF: 0.00941

Gnomad AMR exome AF: 0.0410

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.127

Gnomad FIN exome AF: 0.0225

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0311

GnomAD4 exome AF: 0.0263 AC: 38512 AN: 1461864 Hom.: 1104 Cov.: 33 AF XY: 0.0276 AC XY: 20051 AN XY: 727228

African (AFR) AF: 0.00956 AC: 320 AN: 33480

American (AMR) AF: 0.0406 AC: 1814 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 361 AN: 26134

East Asian (EAS) AF: 0.160 AC: 6340 AN: 39692

South Asian (SAS) AF: 0.0707 AC: 6100 AN: 86256

European-Finnish (FIN) AF: 0.0215 AC: 1150 AN: 53416

Middle Eastern (MID) AF: 0.0236 AC: 136 AN: 5768

European-Non Finnish (NFE) AF: 0.0185 AC: 20559 AN: 1112002

Other (OTH) AF: 0.0287 AC: 1732 AN: 60392

GnomAD4 genome AF: 0.0247 AC: 3767 AN: 152220 Hom.: 99 Cov.: 32 AF XY: 0.0260 AC XY: 1936 AN XY: 74430

African (AFR) AF: 0.0104 AC: 432 AN: 41542

American (AMR) AF: 0.0431 AC: 659 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3466

East Asian (EAS) AF: 0.129 AC: 668 AN: 5162

South Asian (SAS) AF: 0.0722 AC: 348 AN: 4822

European-Finnish (FIN) AF: 0.0206 AC: 219 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0196 AC: 1332 AN: 68016

Other (OTH) AF: 0.0270 AC: 57 AN: 2114

Alfa AF: 0.0234 Hom.: 442

Bravo AF: 0.0254

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0208 AC: 80

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.0201 AC: 173

ExAC AF: 0.0364 AC: 4418

Asia WGS AF: 0.0910 AC: 315 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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.

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 23, 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.

not provided Benign:2

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely 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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive ataxia, Beauce type Benign:1

Jan 12, 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 12, 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.8
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.45
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.016
Sift	Benign	0.10	T
Sift4G	Benign	0.10	T
Polyphen		0.050	B
Vest4		0.16
MPC		0.16
ClinPred		0.0046	T
GERP RS		2.3
Varity_R		0.095
gMVP		0.071
Mutation Taster		=98/2	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs13210127; hg19: chr6-152671865; COSMIC: COSV107319801;