rs214950

Variant names:

• chr6-152387175-G-A
• rs214950
• NM_182961.4:c.8384C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-152387175-G-A
• chr6-152387175-G-C
• chr6-152387175-G-T

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.8384C>T​(p.Ala2795Val) variant causes a missense change. The variant allele was found at a frequency of 0.225 in 1,613,860 control chromosomes in the GnomAD database, including 43,125 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2795A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.21 (3516 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39609 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.58
• Publications: 46 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=0.0038202405).
• BP6: Variant 6-152387175-G-A is Benign according to our data. Variant chr6-152387175-G-A is described in ClinVar as Benign. ClinVar VariationId is 130452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.399 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.8384C>T	p.Ala2795Val	missense	Exon 54 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.8405C>T	p.Ala2802Val	missense	Exon 54 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.8384C>T	p.Ala2795Val	missense	Exon 54 of 146	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.8405C>T	p.Ala2802Val	missense	Exon 54 of 146	ENSP00000396024.1
	SYNE1	ENST00000461872.6	TSL:1	n.8602C>T		non_coding_transcript_exon	Exon 52 of 55

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31223 AN: 151926 Hom.: 3517 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.226

GnomAD2 exomes AF: 0.235 AC: 59044 AN: 250998 AF XY: 0.242

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.421

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.227 AC: 331936 AN: 1461814 Hom.: 39609 Cov.: 34 AF XY: 0.230 AC XY: 167568 AN XY: 727198

African (AFR) AF: 0.151 AC: 5064 AN: 33476

American (AMR) AF: 0.188 AC: 8420 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5328 AN: 26136

East Asian (EAS) AF: 0.426 AC: 16928 AN: 39694

South Asian (SAS) AF: 0.311 AC: 26816 AN: 86256

European-Finnish (FIN) AF: 0.188 AC: 10065 AN: 53420

Middle Eastern (MID) AF: 0.306 AC: 1763 AN: 5760

European-Non Finnish (NFE) AF: 0.219 AC: 243469 AN: 1111956

Other (OTH) AF: 0.233 AC: 14083 AN: 60394

GnomAD4 genome AF: 0.205 AC: 31231 AN: 152046 Hom.: 3516 Cov.: 32 AF XY: 0.206 AC XY: 15317 AN XY: 74304

African (AFR) AF: 0.154 AC: 6372 AN: 41472

American (AMR) AF: 0.185 AC: 2821 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 748 AN: 3468

East Asian (EAS) AF: 0.414 AC: 2134 AN: 5156

South Asian (SAS) AF: 0.319 AC: 1535 AN: 4814

European-Finnish (FIN) AF: 0.183 AC: 1932 AN: 10560

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 15024 AN: 67976

Other (OTH) AF: 0.227 AC: 480 AN: 2114

Alfa AF: 0.221 Hom.: 19133

Bravo AF: 0.203

TwinsUK AF: 0.222 AC: 825

ALSPAC AF: 0.216 AC: 832

ESP6500AA AF: 0.158 AC: 698

ESP6500EA AF: 0.219 AC: 1883

ExAC AF: 0.237 AC: 28800

Asia WGS AF: 0.325 AC: 1131 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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	0.090
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.31
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.80
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M
PhyloP100		4.6
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.10
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.019	D
Polyphen		0.033	B
Vest4		0.18
MPC		0.13
ClinPred		0.030	T
GERP RS		1.5
Varity_R		0.042
gMVP		0.045
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: rs214950; hg19: chr6-152708310; COSMIC: COSV54924746;