6-152308496-C-T

Variant names:

• chr6-152308496-C-T
• rs76160752
• NM_182961.4:c.17339G>A

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.17339G>A​(p.Arg5780Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,614,034 control chromosomes in the GnomAD database, including 349 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (95 hom., cov: 31)
  • Exomes 𝑓: 0.011 (254 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.29
• Publications: 12 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=0.0018066168).
• BP6: Variant 6-152308496-C-T is Benign according to our data. Variant chr6-152308496-C-T is described in ClinVar as Benign. ClinVar VariationId is 130411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0577 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.17339G>A	p.Arg5780Gln	missense	Exon 91 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.17126G>A	p.Arg5709Gln	missense	Exon 90 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.17339G>A	p.Arg5780Gln	missense	Exon 91 of 146	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.17126G>A	p.Arg5709Gln	missense	Exon 90 of 146	ENSP00000396024.1
	SYNE1	ENST00000367256.9	TSL:1	n.1031G>A		non_coding_transcript_exon	Exon 6 of 61

Frequencies

GnomAD3 genomes AF: 0.0267 AC: 4061 AN: 152062 Hom.: 96 Cov.: 31

Gnomad AFR AF: 0.0596

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0374

Gnomad ASJ AF: 0.0309

Gnomad EAS AF: 0.0392

Gnomad SAS AF: 0.0349

Gnomad FIN AF: 0.00208

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00662

Gnomad OTH AF: 0.0311

GnomAD2 exomes AF: 0.0195 AC: 4914 AN: 251464 AF XY: 0.0192

Gnomad AFR exome AF: 0.0581

Gnomad AMR exome AF: 0.0261

Gnomad ASJ exome AF: 0.0313

Gnomad EAS exome AF: 0.0394

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00669

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0105 AC: 15414 AN: 1461856 Hom.: 254 Cov.: 50 AF XY: 0.0113 AC XY: 8229 AN XY: 727226

African (AFR) AF: 0.0572 AC: 1915 AN: 33480

American (AMR) AF: 0.0291 AC: 1300 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0336 AC: 879 AN: 26136

East Asian (EAS) AF: 0.0296 AC: 1174 AN: 39698

South Asian (SAS) AF: 0.0363 AC: 3129 AN: 86254

European-Finnish (FIN) AF: 0.00247 AC: 132 AN: 53406

Middle Eastern (MID) AF: 0.0267 AC: 154 AN: 5768

European-Non Finnish (NFE) AF: 0.00519 AC: 5768 AN: 1112000

Other (OTH) AF: 0.0159 AC: 963 AN: 60392

GnomAD4 genome AF: 0.0268 AC: 4077 AN: 152178 Hom.: 95 Cov.: 31 AF XY: 0.0275 AC XY: 2048 AN XY: 74386

African (AFR) AF: 0.0597 AC: 2480 AN: 41538

American (AMR) AF: 0.0376 AC: 574 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0309 AC: 107 AN: 3468

East Asian (EAS) AF: 0.0389 AC: 201 AN: 5166

South Asian (SAS) AF: 0.0341 AC: 164 AN: 4812

European-Finnish (FIN) AF: 0.00208 AC: 22 AN: 10590

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.00665 AC: 452 AN: 68010

Other (OTH) AF: 0.0322 AC: 68 AN: 2112

Alfa AF: 0.0136 Hom.: 135

Bravo AF: 0.0308

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.0626 AC: 276

ESP6500EA AF: 0.00709 AC: 61

ExAC AF: 0.0196 AC: 2379

Asia WGS AF: 0.0410 AC: 141 AN: 3478

EpiCase AF: 0.00834

EpiControl AF: 0.00788

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.3
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.018
Sift	Benign	0.062	T
Sift4G	Benign	0.11	T
Polyphen		0.38	B
Vest4		0.14
MPC		0.59
ClinPred		0.036	T
GERP RS		3.2
Varity_R		0.060
gMVP		0.11
Mutation Taster		=97/3	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs76160752; hg19: chr6-152629631; COSMIC: COSV54970360;