rs146001055

Variant names:

• chr6-152462768-C-T
• rs146001055
• NM_182961.4:c.2220G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_182961.4(SYNE1):​c.2220G>A​(p.Met740Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000671 in 1,613,996 control chromosomes in the GnomAD database, including 9 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 0.0037 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (4 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.73
• Publications: 1 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025467873).
• BP6: Variant 6-152462768-C-T is Benign according to our data. Variant chr6-152462768-C-T is described in ClinVar as Benign. ClinVar VariationId is 355936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 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.2220G>A	p.Met740Ile	missense	Exon 20 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.2241G>A	p.Met747Ile	missense	Exon 20 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.2220G>A	p.Met740Ile	missense	Exon 20 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.2241G>A	p.Met747Ile	missense	Exon 20 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000466159.6	TSL:1	c.2220G>A	p.Met740Ile	missense	Exon 18 of 18	ENSP00000446021.1	F5H4Q0

Frequencies

GnomAD3 genomes AF: 0.00374 AC: 569 AN: 152134 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000936 AC: 235 AN: 251112 AF XY: 0.000597

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000353 AC: 516 AN: 1461744 Hom.: 4 Cov.: 32 AF XY: 0.000282 AC XY: 205 AN XY: 727172

African (AFR) AF: 0.0130 AC: 434 AN: 33474

American (AMR) AF: 0.000604 AC: 27 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111930

Other (OTH) AF: 0.000878 AC: 53 AN: 60390

GnomAD4 genome AF: 0.00372 AC: 567 AN: 152252 Hom.: 5 Cov.: 32 AF XY: 0.00363 AC XY: 270 AN XY: 74452

African (AFR) AF: 0.0131 AC: 546 AN: 41546

American (AMR) AF: 0.000719 AC: 11 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68008

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00145 Hom.: 4

Bravo AF: 0.00467

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00130 AC: 158

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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 specified (1)
-	-	1	SYNE1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.70
DANN	Benign	0.87
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.3	N
PhyloP100		-2.7
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.073
Sift	Benign	0.20	T
Sift4G	Benign	0.067	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.40		Gain of catalytic residue at L745 (P = 0.0558)
MVP		0.38
MPC		0.15
ClinPred		0.0089	T
GERP RS		-9.1
Varity_R		0.088
gMVP		0.040
Mutation Taster		=97/3	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs146001055; hg19: chr6-152783903;