rs17082236

Variant names:

• chr6-152149617-C-A
• rs17082236
• NM_182961.4:c.24502G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-152149617-C-A
• chr6-152149617-C-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.24502G>T​(p.Ala8168Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0602 in 1,613,862 control chromosomes in the GnomAD database, including 5,404 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A8168D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (1995 hom., cov: 32)
  • Exomes 𝑓: 0.054 (3409 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.57
• Publications: 18 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

ENSG00000300811 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038188696).
• BP6: Variant 6-152149617-C-A is Benign according to our data. Variant chr6-152149617-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 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.24502G>T	p.Ala8168Ser	missense	Exon 136 of 146	NP_892006.3
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.967G>T	p.Ala323Ser	missense	Exon 7 of 18	NP_001334631.1
	SYNE1	NM_033071.5		c.24289G>T	p.Ala8097Ser	missense	Exon 135 of 146	NP_149062.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.24502G>T	p.Ala8168Ser	missense	Exon 136 of 146	ENSP00000356224.5
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.967G>T	p.Ala323Ser	missense	Exon 7 of 18	ENSP00000346701.4
	SYNE1	ENST00000423061.6	TSL:1	c.24289G>T	p.Ala8097Ser	missense	Exon 135 of 146	ENSP00000396024.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18087 AN: 151924 Hom.: 1993 Cov.: 32

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0937

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0278

Gnomad FIN AF: 0.0404

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0495

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.0646 AC: 16253 AN: 251452 AF XY: 0.0597

Gnomad AFR exome AF: 0.298

Gnomad AMR exome AF: 0.0560

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.0420

Gnomad NFE exome AF: 0.0541

Gnomad OTH exome AF: 0.0681

GnomAD4 exome AF: 0.0540 AC: 79004 AN: 1461820 Hom.: 3409 Cov.: 32 AF XY: 0.0528 AC XY: 38363 AN XY: 727214

African (AFR) AF: 0.292 AC: 9784 AN: 33478

American (AMR) AF: 0.0592 AC: 2646 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2921 AN: 26136

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39700

South Asian (SAS) AF: 0.0291 AC: 2510 AN: 86258

European-Finnish (FIN) AF: 0.0426 AC: 2274 AN: 53408

Middle Eastern (MID) AF: 0.100 AC: 577 AN: 5768

European-Non Finnish (NFE) AF: 0.0486 AC: 54062 AN: 1111954

Other (OTH) AF: 0.0699 AC: 4220 AN: 60394

GnomAD4 genome AF: 0.119 AC: 18115 AN: 152042 Hom.: 1995 Cov.: 32 AF XY: 0.117 AC XY: 8691 AN XY: 74304

African (AFR) AF: 0.290 AC: 12019 AN: 41408

American (AMR) AF: 0.0933 AC: 1426 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5168

South Asian (SAS) AF: 0.0278 AC: 134 AN: 4822

European-Finnish (FIN) AF: 0.0404 AC: 427 AN: 10578

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0495 AC: 3367 AN: 68002

Other (OTH) AF: 0.126 AC: 266 AN: 2112

Alfa AF: 0.0801 Hom.: 2647

Bravo AF: 0.132

TwinsUK AF: 0.0442 AC: 164

ALSPAC AF: 0.0459 AC: 177

ESP6500AA AF: 0.286 AC: 1259

ESP6500EA AF: 0.0548 AC: 471

ExAC AF: 0.0678 AC: 8226

Asia WGS AF: 0.0220 AC: 78 AN: 3478

EpiCase AF: 0.0579

EpiControl AF: 0.0630

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.6
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.041
Sift	Benign	0.43	T
Sift4G	Benign	0.43	T
Polyphen		0.0010	B
Vest4		0.16
MPC		0.12
ClinPred		0.011	T
GERP RS		4.0
PromoterAI		-0.012	Neutral
Varity_R		0.15
gMVP		0.11
Mutation Taster		=95/5	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs17082236; hg19: chr6-152470752; COSMIC: COSV54938531; COSMIC: COSV54938531;