rs2306914

Variant names:

• chr6-152318975-G-A
• rs2306914
• NM_182961.4:c.16277C>T

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.16277C>T​(p.Thr5426Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0331 in 1,614,120 control chromosomes in the GnomAD database, including 1,416 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T5426T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (124 hom., cov: 33)
  • Exomes 𝑓: 0.034 (1292 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.908
• Publications: 22 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, PanelApp Australia, G2P
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• arthrogryposis multiplex congenita 3, myogenic type

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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=0.0011658967).
• BP6: Variant 6-152318975-G-A is Benign according to our data. Variant chr6-152318975-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.142 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.16277C>T	p.Thr5426Met	missense	Exon 85 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.16064C>T	p.Thr5355Met	missense	Exon 84 of 146	NP_149062.2	Q8NF91-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.16277C>T	p.Thr5426Met	missense	Exon 85 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.16064C>T	p.Thr5355Met	missense	Exon 84 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000490135.6	TSL:1	n.3623C>T		non_coding_transcript_exon	Exon 9 of 11

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4291 AN: 152164 Hom.: 124 Cov.: 33

Gnomad AFR AF: 0.00649

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.0325

Gnomad FIN AF: 0.0375

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0309

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0410 AC: 10296 AN: 251368 AF XY: 0.0396

Gnomad AFR exome AF: 0.00535

Gnomad AMR exome AF: 0.0493

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.165

Gnomad FIN exome AF: 0.0401

Gnomad NFE exome AF: 0.0295

Gnomad OTH exome AF: 0.0362

GnomAD4 exome AF: 0.0336 AC: 49184 AN: 1461838 Hom.: 1292 Cov.: 32 AF XY: 0.0332 AC XY: 24113 AN XY: 727210

African (AFR) AF: 0.00496 AC: 166 AN: 33480

American (AMR) AF: 0.0489 AC: 2188 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 391 AN: 26132

East Asian (EAS) AF: 0.155 AC: 6155 AN: 39698

South Asian (SAS) AF: 0.0254 AC: 2195 AN: 86252

European-Finnish (FIN) AF: 0.0406 AC: 2169 AN: 53402

Middle Eastern (MID) AF: 0.0264 AC: 152 AN: 5768

European-Non Finnish (NFE) AF: 0.0303 AC: 33710 AN: 1111986

Other (OTH) AF: 0.0341 AC: 2058 AN: 60396

GnomAD4 genome AF: 0.0282 AC: 4287 AN: 152282 Hom.: 124 Cov.: 33 AF XY: 0.0290 AC XY: 2163 AN XY: 74466

African (AFR) AF: 0.00648 AC: 269 AN: 41542

American (AMR) AF: 0.0291 AC: 445 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3468

East Asian (EAS) AF: 0.151 AC: 783 AN: 5184

South Asian (SAS) AF: 0.0323 AC: 156 AN: 4830

European-Finnish (FIN) AF: 0.0375 AC: 398 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0309 AC: 2105 AN: 68026

Other (OTH) AF: 0.0284 AC: 60 AN: 2112

Alfa AF: 0.0307 Hom.: 393

Bravo AF: 0.0282

TwinsUK AF: 0.0297 AC: 110

ALSPAC AF: 0.0317 AC: 122

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0272 AC: 234

ExAC AF: 0.0393 AC: 4768

Asia WGS AF: 0.0770 AC: 267 AN: 3478

EpiCase AF: 0.0281

EpiControl AF: 0.0261

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Autosomal recessive ataxia, Beauce type (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.61
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N
PhyloP100		0.91
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.053
Sift	Benign	0.19	T
Sift4G	Benign	0.57	T
Polyphen		0.0010	B
Vest4		0.062
MPC		0.14
ClinPred		0.0087	T
GERP RS		0.29
Varity_R		0.023
gMVP		0.082
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: rs2306914; hg19: chr6-152640110; COSMIC: COSV54935615; COSMIC: COSV54935615;