rs2306916

Variant names:

• chr6-152326546-A-T
• rs2306916
• NM_182961.4:c.15043T>A

Your query was ambiguous. Multiple possible variants found:

• chr6-152326546-A-T
• chr6-152326546-A-C
• chr6-152326546-A-G

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.15043T>A​(p.Leu5015Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,614,054 control chromosomes in the GnomAD database, including 476,515 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L5015L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.81 (50926 hom., cov: 33)
  • Exomes 𝑓: 0.76 (425589 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.93
• Publications: 44 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=5.5081324E-7).
• BP6: Variant 6-152326546-A-T is Benign according to our data. Variant chr6-152326546-A-T is described in ClinVar as Benign. ClinVar VariationId is 130408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.924 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.15043T>A	p.Leu5015Met	missense	Exon 79 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.14830T>A	p.Leu4944Met	missense	Exon 78 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.15043T>A	p.Leu5015Met	missense	Exon 79 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.14830T>A	p.Leu4944Met	missense	Exon 78 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000490135.6	TSL:1	n.2389T>A		non_coding_transcript_exon	Exon 3 of 11

Frequencies

GnomAD3 genomes AF: 0.814 AC: 123789 AN: 152076 Hom.: 50859 Cov.: 33

Gnomad AFR AF: 0.932

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.819

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.838

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.845

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.755

Gnomad OTH AF: 0.777

GnomAD2 exomes AF: 0.782 AC: 196687 AN: 251392 AF XY: 0.768

Gnomad AFR exome AF: 0.935

Gnomad AMR exome AF: 0.869

Gnomad ASJ exome AF: 0.713

Gnomad EAS exome AF: 0.840

Gnomad FIN exome AF: 0.850

Gnomad NFE exome AF: 0.756

Gnomad OTH exome AF: 0.762

GnomAD4 exome AF: 0.761 AC: 1112468 AN: 1461860 Hom.: 425589 Cov.: 67 AF XY: 0.756 AC XY: 549715 AN XY: 727234

African (AFR) AF: 0.934 AC: 31272 AN: 33480

American (AMR) AF: 0.864 AC: 38642 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.715 AC: 18694 AN: 26136

East Asian (EAS) AF: 0.846 AC: 33601 AN: 39700

South Asian (SAS) AF: 0.649 AC: 55986 AN: 86256

European-Finnish (FIN) AF: 0.846 AC: 45176 AN: 53416

Middle Eastern (MID) AF: 0.635 AC: 3664 AN: 5768

European-Non Finnish (NFE) AF: 0.755 AC: 839759 AN: 1111988

Other (OTH) AF: 0.756 AC: 45674 AN: 60394

GnomAD4 genome AF: 0.814 AC: 123914 AN: 152194 Hom.: 50926 Cov.: 33 AF XY: 0.817 AC XY: 60757 AN XY: 74396

African (AFR) AF: 0.932 AC: 38726 AN: 41552

American (AMR) AF: 0.819 AC: 12522 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 2429 AN: 3470

East Asian (EAS) AF: 0.837 AC: 4311 AN: 5150

South Asian (SAS) AF: 0.651 AC: 3138 AN: 4818

European-Finnish (FIN) AF: 0.845 AC: 8951 AN: 10588

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.755 AC: 51339 AN: 68002

Other (OTH) AF: 0.780 AC: 1650 AN: 2116

Alfa AF: 0.761 Hom.: 33126

Bravo AF: 0.819

TwinsUK AF: 0.743 AC: 2756

ALSPAC AF: 0.768 AC: 2961

ESP6500AA AF: 0.930 AC: 4096

ESP6500EA AF: 0.749 AC: 6445

ExAC AF: 0.779 AC: 94634

Asia WGS AF: 0.779 AC: 2710 AN: 3478

EpiCase AF: 0.733

EpiControl AF: 0.734

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Autosomal recessive ataxia, Beauce type (2)
-	-	2	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (2)
-	-	1	Arthrogryposis multiplex congenita 3, myogenic type (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807: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	0.066
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	17
DANN	Benign	0.78
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.034	T
MetaRNN	Benign	5.5e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.17	N
PhyloP100		2.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.027
Sift	Benign	0.61	T
Sift4G	Benign	0.40	T
Polyphen		0.0020	B
Vest4		0.083
MPC		0.13
ClinPred		0.0041	T
GERP RS		3.2
Varity_R		0.067
gMVP		0.059
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2306916; hg19: chr6-152647681; COSMIC: COSV54950581;