rs17082709

Variant names:

• chr6-152455960-A-C
• rs17082709
• NM_182961.4:c.2653T>G

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.2653T>G​(p.Leu885Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0592 in 1,614,058 control chromosomes in the GnomAD database, including 3,084 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 0.059 (309 hom., cov: 33)
  • Exomes 𝑓: 0.059 (2775 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.06
• Publications: 24 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=0.0016322136).
• BP6: Variant 6-152455960-A-C is Benign according to our data. Variant chr6-152455960-A-C is described in ClinVar as Benign. ClinVar VariationId is 130437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0663 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.2653T>G	p.Leu885Val	missense	Exon 23 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.2674T>G	p.Leu892Val	missense	Exon 23 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.2653T>G	p.Leu885Val	missense	Exon 23 of 146	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.2674T>G	p.Leu892Val	missense	Exon 23 of 146	ENSP00000396024.1
	SYNE1	ENST00000495090.6	TSL:1	c.1354T>G	p.Leu452Val	missense	Exon 10 of 12	ENSP00000438508.1

Frequencies

GnomAD3 genomes AF: 0.0588 AC: 8950 AN: 152138 Hom.: 305 Cov.: 33

Gnomad AFR AF: 0.0516

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0448

Gnomad FIN AF: 0.0531

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0679

Gnomad OTH AF: 0.0737

GnomAD2 exomes AF: 0.0548 AC: 13784 AN: 251376 AF XY: 0.0560

Gnomad AFR exome AF: 0.0544

Gnomad AMR exome AF: 0.0351

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.000924

Gnomad FIN exome AF: 0.0568

Gnomad NFE exome AF: 0.0666

Gnomad OTH exome AF: 0.0610

GnomAD4 exome AF: 0.0592 AC: 86517 AN: 1461802 Hom.: 2775 Cov.: 31 AF XY: 0.0591 AC XY: 42982 AN XY: 727208

African (AFR) AF: 0.0543 AC: 1818 AN: 33480

American (AMR) AF: 0.0375 AC: 1678 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2825 AN: 26130

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39692

South Asian (SAS) AF: 0.0452 AC: 3903 AN: 86256

European-Finnish (FIN) AF: 0.0544 AC: 2905 AN: 53396

Middle Eastern (MID) AF: 0.0648 AC: 374 AN: 5768

European-Non Finnish (NFE) AF: 0.0624 AC: 69349 AN: 1111964

Other (OTH) AF: 0.0605 AC: 3652 AN: 60394

GnomAD4 genome AF: 0.0589 AC: 8966 AN: 152256 Hom.: 309 Cov.: 33 AF XY: 0.0575 AC XY: 4283 AN XY: 74450

African (AFR) AF: 0.0519 AC: 2156 AN: 41540

American (AMR) AF: 0.0567 AC: 867 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 363 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5186

South Asian (SAS) AF: 0.0446 AC: 215 AN: 4816

European-Finnish (FIN) AF: 0.0531 AC: 564 AN: 10620

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0679 AC: 4619 AN: 68014

Other (OTH) AF: 0.0724 AC: 153 AN: 2112

Alfa AF: 0.0628 Hom.: 772

Bravo AF: 0.0581

TwinsUK AF: 0.0604 AC: 224

ALSPAC AF: 0.0584 AC: 225

ESP6500AA AF: 0.0545 AC: 240

ESP6500EA AF: 0.0679 AC: 584

ExAC AF: 0.0556 AC: 6747

Asia WGS AF: 0.0360 AC: 123 AN: 3478

EpiCase AF: 0.0680

EpiControl AF: 0.0680

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.1
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.028
Sift	Benign	0.24	T
Sift4G	Benign	0.28	T
Polyphen		0.055	B
Vest4		0.040
MPC		0.13
ClinPred		0.0029	T
GERP RS		1.5
Varity_R		0.048
gMVP		0.065
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs17082709; hg19: chr6-152777095; COSMIC: COSV55119781; COSMIC: COSV55119781;