rs76646638

Variant names:

• chr6-152455436-C-T
• rs76646638
• NM_182961.4:c.2882G>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.2882G>A​(p.Arg961Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,613,946 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R961W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (5 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0790
• 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: 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005189121).
• BP6: Variant 6-152455436-C-T is Benign according to our data. Variant chr6-152455436-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.2882G>A	p.Arg961Gln	missense	Exon 24 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.2903G>A	p.Arg968Gln	missense	Exon 24 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.2882G>A	p.Arg961Gln	missense	Exon 24 of 146	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.2903G>A	p.Arg968Gln	missense	Exon 24 of 146	ENSP00000396024.1
	SYNE1	ENST00000495090.6	TSL:1	c.1583G>A	p.Arg528Gln	missense	Exon 11 of 12	ENSP00000438508.1

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 440 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00131 AC: 328 AN: 251014 AF XY: 0.00116

Gnomad AFR exome AF: 0.00745

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00116 AC: 1702 AN: 1461672 Hom.: 5 Cov.: 31 AF XY: 0.00108 AC XY: 788 AN XY: 727136

African (AFR) AF: 0.00887 AC: 297 AN: 33466

American (AMR) AF: 0.000783 AC: 35 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86246

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53400

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00113 AC: 1251 AN: 1111868

Other (OTH) AF: 0.00144 AC: 87 AN: 60394

GnomAD4 genome AF: 0.00290 AC: 442 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.00240 AC XY: 179 AN XY: 74450

African (AFR) AF: 0.00749 AC: 311 AN: 41546

American (AMR) AF: 0.00209 AC: 32 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68040

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00172 Hom.: 0

Bravo AF: 0.00296

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00175 AC: 212

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00113

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	2	not specified (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)
-	-	1	SYNE1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.045	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.079
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.086
Sift	Benign	0.050	D
Sift4G	Uncertain	0.013	D
Polyphen		0.49	P
Vest4		0.28
MVP		0.23
MPC		0.18
ClinPred		0.028	T
GERP RS		-3.3
Varity_R		0.058
gMVP		0.057
Mutation Taster		=91/9	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs76646638; hg19: chr6-152776571; COSMIC: COSV54952107; COSMIC: COSV54952107;