chr6-152132156-G-A

Variant names:

• chr6-152132156-G-A
• rs35591210
• NM_182961.4:c.26060C>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.26060C>T​(p.Thr8687Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,613,876 control chromosomes in the GnomAD database, including 4,295 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 0.050 (240 hom., cov: 32)
  • Exomes 𝑓: 0.070 (4055 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.82
• Publications: 20 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

ENSG00000300811 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016930401).
• BP6: Variant 6-152132156-G-A is Benign according to our data. Variant chr6-152132156-G-A is described in ClinVar as Benign. ClinVar VariationId is 130433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0764 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.26060C>T	p.Thr8687Ile	missense	Exon 144 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.2594C>T	p.Thr865Ile	missense	Exon 16 of 18	NP_001334631.1	F8WAI0
	SYNE1	NM_033071.5		c.25916C>T	p.Thr8639Ile	missense	Exon 144 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.26060C>T	p.Thr8687Ile	missense	Exon 144 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.2594C>T	p.Thr865Ile	missense	Exon 16 of 18	ENSP00000346701.4	F8WAI0
	SYNE1	ENST00000423061.6	TSL:1	c.25916C>T	p.Thr8639Ile	missense	Exon 144 of 146	ENSP00000396024.1	A0A0C4DG40

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7575 AN: 152152 Hom.: 240 Cov.: 32

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0430

Gnomad ASJ AF: 0.0481

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0568

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0782

Gnomad OTH AF: 0.0498

GnomAD2 exomes AF: 0.0510 AC: 12818 AN: 251494 AF XY: 0.0518

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.0341

Gnomad ASJ exome AF: 0.0449

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0593

Gnomad NFE exome AF: 0.0769

Gnomad OTH exome AF: 0.0497

GnomAD4 exome AF: 0.0699 AC: 102202 AN: 1461606 Hom.: 4055 Cov.: 31 AF XY: 0.0686 AC XY: 49910 AN XY: 727130

African (AFR) AF: 0.0109 AC: 366 AN: 33478

American (AMR) AF: 0.0339 AC: 1518 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0489 AC: 1278 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0222 AC: 1919 AN: 86256

European-Finnish (FIN) AF: 0.0593 AC: 3167 AN: 53414

Middle Eastern (MID) AF: 0.0362 AC: 209 AN: 5768

European-Non Finnish (NFE) AF: 0.0809 AC: 89911 AN: 1111744

Other (OTH) AF: 0.0634 AC: 3830 AN: 60386

GnomAD4 genome AF: 0.0497 AC: 7570 AN: 152270 Hom.: 240 Cov.: 32 AF XY: 0.0477 AC XY: 3555 AN XY: 74460

African (AFR) AF: 0.0133 AC: 552 AN: 41566

American (AMR) AF: 0.0429 AC: 656 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0481 AC: 167 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4818

European-Finnish (FIN) AF: 0.0568 AC: 603 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0782 AC: 5315 AN: 68004

Other (OTH) AF: 0.0488 AC: 103 AN: 2110

Alfa AF: 0.0659 Hom.: 943

Bravo AF: 0.0478

TwinsUK AF: 0.0801 AC: 297

ALSPAC AF: 0.0823 AC: 317

ESP6500AA AF: 0.0152 AC: 67

ESP6500EA AF: 0.0745 AC: 641

ExAC AF: 0.0513 AC: 6234

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0793

EpiControl AF: 0.0737

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	0.093
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.8
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.073
Sift	Benign	0.061	T
Sift4G	Uncertain	0.010	D
Polyphen		0.0040	B
Vest4		0.26
MPC		0.14
ClinPred		0.0074	T
GERP RS		2.6
Varity_R		0.029
gMVP		0.22
Mutation Taster		=84/16	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs35591210; hg19: chr6-152453291; COSMIC: COSV107319210; COSMIC: COSV107319210;