rs4645434

Variant names:

• chr6-152344126-C-A
• rs4645434
• NM_182961.4:c.12180G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-152344126-C-A
• chr6-152344126-C-G
• chr6-152344126-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.12180G>T​(p.Glu4060Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,613,888 control chromosomes in the GnomAD database, including 292,794 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24306 hom., cov: 32)
  • Exomes 𝑓: 0.60 (268488 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.394
• Publications: 49 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=1.2501399E-5).
• BP6: Variant 6-152344126-C-A is Benign according to our data. Variant chr6-152344126-C-A is described in ClinVar as Benign. ClinVar VariationId is 130397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.622 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.12180G>T	p.Glu4060Asp	missense	Exon 74 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.11967G>T	p.Glu3989Asp	missense	Exon 73 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.12180G>T	p.Glu4060Asp	missense	Exon 74 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.11967G>T	p.Glu3989Asp	missense	Exon 73 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000471834.1	TSL:1	n.5318G>T		non_coding_transcript_exon	Exon 17 of 19

Frequencies

GnomAD3 genomes AF: 0.560 AC: 85068 AN: 151952 Hom.: 24292 Cov.: 32

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.604

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.528

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.580

GnomAD2 exomes AF: 0.583 AC: 146655 AN: 251458 AF XY: 0.582

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.600

Gnomad ASJ exome AF: 0.653

Gnomad EAS exome AF: 0.639

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.608

Gnomad OTH exome AF: 0.589

GnomAD4 exome AF: 0.604 AC: 883635 AN: 1461816 Hom.: 268488 Cov.: 64 AF XY: 0.602 AC XY: 437602 AN XY: 727206

African (AFR) AF: 0.439 AC: 14691 AN: 33478

American (AMR) AF: 0.601 AC: 26893 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 17172 AN: 26134

East Asian (EAS) AF: 0.645 AC: 25606 AN: 39696

South Asian (SAS) AF: 0.514 AC: 44339 AN: 86258

European-Finnish (FIN) AF: 0.546 AC: 29177 AN: 53406

Middle Eastern (MID) AF: 0.522 AC: 3009 AN: 5764

European-Non Finnish (NFE) AF: 0.618 AC: 686712 AN: 1111964

Other (OTH) AF: 0.597 AC: 36036 AN: 60396

GnomAD4 genome AF: 0.560 AC: 85124 AN: 152072 Hom.: 24306 Cov.: 32 AF XY: 0.556 AC XY: 41303 AN XY: 74312

African (AFR) AF: 0.449 AC: 18618 AN: 41462

American (AMR) AF: 0.605 AC: 9252 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 2252 AN: 3466

East Asian (EAS) AF: 0.640 AC: 3302 AN: 5156

South Asian (SAS) AF: 0.527 AC: 2543 AN: 4830

European-Finnish (FIN) AF: 0.534 AC: 5637 AN: 10564

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.612 AC: 41624 AN: 67988

Other (OTH) AF: 0.582 AC: 1230 AN: 2112

Alfa AF: 0.598 Hom.: 135593

Bravo AF: 0.562

TwinsUK AF: 0.608 AC: 2255

ALSPAC AF: 0.629 AC: 2423

ESP6500AA AF: 0.469 AC: 2065

ESP6500EA AF: 0.618 AC: 5313

ExAC AF: 0.576 AC: 69938

Asia WGS AF: 0.593 AC: 2064 AN: 3478

EpiCase AF: 0.602

EpiControl AF: 0.597

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	0.11
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.9
DANN	Benign	0.15
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.000013	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.39
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.058
Sift	Benign	0.071	T
Sift4G	Uncertain	0.042	D
Polyphen		0.20	B
Vest4		0.13
MutPred		0.089		Loss of helix (P = 0.028)
MPC		0.13
ClinPred		0.0067	T
GERP RS		-1.3
Varity_R		0.054
gMVP		0.088
Mutation Taster		=96/4	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4645434; hg19: chr6-152665261; COSMIC: COSV54944935;