rs12664753

Variant names:

• chr6-152294065-G-A
• rs12664753
• NM_182961.4:c.17745C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-152294065-G-A
• chr6-152294065-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182961.4(SYNE1):​c.17745C>T​(p.His5915His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,613,740 control chromosomes in the GnomAD database, including 30,213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2201 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28012 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.284
• 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-152294065-G-A is Benign according to our data. Variant chr6-152294065-G-A is described in ClinVar as Benign. ClinVar VariationId is 130414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.284 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.222 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.17745C>T	p.His5915His	synonymous	Exon 94 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.17532C>T	p.His5844His	synonymous	Exon 93 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.17745C>T	p.His5915His	synonymous	Exon 94 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.17532C>T	p.His5844His	synonymous	Exon 93 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000367256.9	TSL:1	n.1437C>T		non_coding_transcript_exon	Exon 9 of 61

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22850 AN: 152016 Hom.: 2203 Cov.: 32

Gnomad AFR AF: 0.0362

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.190 AC: 47774 AN: 251352 AF XY: 0.192

Gnomad AFR exome AF: 0.0339

Gnomad AMR exome AF: 0.220

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.189

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.191 AC: 279614 AN: 1461606 Hom.: 28012 Cov.: 35 AF XY: 0.192 AC XY: 139472 AN XY: 727100

African (AFR) AF: 0.0296 AC: 991 AN: 33472

American (AMR) AF: 0.211 AC: 9423 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3644 AN: 26132

East Asian (EAS) AF: 0.182 AC: 7224 AN: 39700

South Asian (SAS) AF: 0.214 AC: 18466 AN: 86246

European-Finnish (FIN) AF: 0.235 AC: 12558 AN: 53414

Middle Eastern (MID) AF: 0.123 AC: 690 AN: 5608

European-Non Finnish (NFE) AF: 0.194 AC: 216032 AN: 1111944

Other (OTH) AF: 0.175 AC: 10586 AN: 60376

GnomAD4 genome AF: 0.150 AC: 22846 AN: 152134 Hom.: 2201 Cov.: 32 AF XY: 0.154 AC XY: 11480 AN XY: 74358

African (AFR) AF: 0.0361 AC: 1499 AN: 41544

American (AMR) AF: 0.171 AC: 2618 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 506 AN: 3472

East Asian (EAS) AF: 0.186 AC: 959 AN: 5164

South Asian (SAS) AF: 0.233 AC: 1124 AN: 4820

European-Finnish (FIN) AF: 0.233 AC: 2456 AN: 10560

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13079 AN: 67972

Other (OTH) AF: 0.136 AC: 287 AN: 2110

Alfa AF: 0.169 Hom.: 3949

Bravo AF: 0.140

Asia WGS AF: 0.168 AC: 584 AN: 3478

EpiCase AF: 0.186

EpiControl AF: 0.184

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.28
DANN	Benign	0.36
PhyloP100		-0.28
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: rs12664753; hg19: chr6-152615200; COSMIC: COSV54924635;