rs117501809

Variant names:

• chr6-152336927-C-G
• rs117501809
• NM_182961.4:c.12442G>C

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.12442G>C​(p.Asp4148His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0306 in 1,614,180 control chromosomes in the GnomAD database, including 913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D4148D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (45 hom., cov: 32)
  • Exomes 𝑓: 0.031 (868 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.90
• Publications: 13 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=0.0064047575).
• BP6: Variant 6-152336927-C-G is Benign according to our data. Variant chr6-152336927-C-G is described in ClinVar as Benign. ClinVar VariationId is 130401.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 = 0.0219 (3339/152338) while in subpopulation NFE AF = 0.0344 (2343/68036). AF 95% confidence interval is 0.0333. There are 45 homozygotes in GnomAd4. There are 1570 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 AR,AD 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.12442G>C	p.Asp4148His	missense	Exon 76 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.12229G>C	p.Asp4077His	missense	Exon 75 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.12442G>C	p.Asp4148His	missense	Exon 76 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.12229G>C	p.Asp4077His	missense	Exon 75 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000471834.1	TSL:1	n.5580G>C		non_coding_transcript_exon	Exon 19 of 19

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3339 AN: 152220 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.00511

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.0322

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0253 AC: 6362 AN: 251382 AF XY: 0.0267

Gnomad AFR exome AF: 0.00597

Gnomad AMR exome AF: 0.00966

Gnomad ASJ exome AF: 0.00893

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0314

Gnomad NFE exome AF: 0.0355

Gnomad OTH exome AF: 0.0257

GnomAD4 exome AF: 0.0315 AC: 46007 AN: 1461842 Hom.: 868 Cov.: 29 AF XY: 0.0315 AC XY: 22885 AN XY: 727222

African (AFR) AF: 0.00493 AC: 165 AN: 33480

American (AMR) AF: 0.0101 AC: 450 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00899 AC: 235 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0319 AC: 2753 AN: 86258

European-Finnish (FIN) AF: 0.0308 AC: 1644 AN: 53378

Middle Eastern (MID) AF: 0.0316 AC: 182 AN: 5768

European-Non Finnish (NFE) AF: 0.0350 AC: 38928 AN: 1112004

Other (OTH) AF: 0.0273 AC: 1648 AN: 60396

GnomAD4 genome AF: 0.0219 AC: 3339 AN: 152338 Hom.: 45 Cov.: 32 AF XY: 0.0211 AC XY: 1570 AN XY: 74492

African (AFR) AF: 0.00510 AC: 212 AN: 41588

American (AMR) AF: 0.0116 AC: 178 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0280 AC: 135 AN: 4830

European-Finnish (FIN) AF: 0.0322 AC: 342 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0344 AC: 2343 AN: 68036

Other (OTH) AF: 0.0161 AC: 34 AN: 2106

Alfa AF: 0.0287 Hom.: 60

Bravo AF: 0.0192

TwinsUK AF: 0.0345 AC: 128

ALSPAC AF: 0.0324 AC: 125

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.0326 AC: 280

ExAC AF: 0.0272 AC: 3298

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0343

EpiControl AF: 0.0319

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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	Pathogenic	0.64
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.68
MPC		0.66
ClinPred		0.011	T
GERP RS		5.5
Varity_R		0.58
gMVP		0.46
Mutation Taster		=92/8	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs117501809; hg19: chr6-152658062; COSMIC: COSV99560137; COSMIC: COSV99560137;