NM_182961.4:c.2527C>T

Variant names:

• chr6-152458798-G-A
• rs34610829
• NM_182961.4:c.2527C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182961.4(SYNE1):​c.2527C>T​(p.Arg843Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0267 in 1,613,920 control chromosomes in the GnomAD database, including 681 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R843H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (46 hom., cov: 32)
  • Exomes 𝑓: 0.027 (635 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.32
• Publications: 18 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=0.002840966).
• BP6: Variant 6-152458798-G-A is Benign according to our data. Variant chr6-152458798-G-A is described in ClinVar as Benign. ClinVar VariationId is 130431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0218 (3317/152204) while in subpopulation NFE AF = 0.0331 (2250/67996). AF 95% confidence interval is 0.032. There are 46 homozygotes in GnomAd4. There are 1582 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 AD,AR gene

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.2527C>T	p.Arg843Cys	missense	Exon 22 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.2548C>T	p.Arg850Cys	missense	Exon 22 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.2527C>T	p.Arg843Cys	missense	Exon 22 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.2548C>T	p.Arg850Cys	missense	Exon 22 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000495090.6	TSL:1	c.1228C>T	p.Arg410Cys	missense	Exon 9 of 12	ENSP00000438508.1	F5H422

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3317 AN: 152086 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.00579

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0233

Gnomad FIN AF: 0.0212

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0331

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.0245 AC: 6165 AN: 251122 AF XY: 0.0256

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.0245

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.0341

Gnomad OTH exome AF: 0.0302

GnomAD4 exome AF: 0.0272 AC: 39729 AN: 1461716 Hom.: 635 Cov.: 32 AF XY: 0.0277 AC XY: 20146 AN XY: 727172

African (AFR) AF: 0.00493 AC: 165 AN: 33464

American (AMR) AF: 0.0184 AC: 823 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0246 AC: 642 AN: 26130

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39686

South Asian (SAS) AF: 0.0252 AC: 2170 AN: 86256

European-Finnish (FIN) AF: 0.0188 AC: 1002 AN: 53416

Middle Eastern (MID) AF: 0.0463 AC: 267 AN: 5764

European-Non Finnish (NFE) AF: 0.0298 AC: 33093 AN: 1111898

Other (OTH) AF: 0.0258 AC: 1561 AN: 60388

GnomAD4 genome AF: 0.0218 AC: 3317 AN: 152204 Hom.: 46 Cov.: 32 AF XY: 0.0213 AC XY: 1582 AN XY: 74414

African (AFR) AF: 0.00578 AC: 240 AN: 41538

American (AMR) AF: 0.0214 AC: 327 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0233 AC: 112 AN: 4812

European-Finnish (FIN) AF: 0.0212 AC: 225 AN: 10600

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0331 AC: 2250 AN: 67996

Other (OTH) AF: 0.0270 AC: 57 AN: 2112

Alfa AF: 0.0295 Hom.: 275

Bravo AF: 0.0206

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0291 AC: 112

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.0312 AC: 268

ExAC AF: 0.0251 AC: 3050

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

ClinVar submissions

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	0.088
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.3
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.14
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.052	T
Polyphen		0.92	P
Vest4		0.21
MPC		0.32
ClinPred		0.014	T
GERP RS		5.3
PromoterAI		-0.039	Neutral
Varity_R		0.15
gMVP		0.084
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: rs34610829; hg19: chr6-152779933; COSMIC: COSV99037530; COSMIC: COSV99037530;