rs2256135

Variant names:

• chr6-152143704-A-G
• rs2256135
• NM_182961.4:c.25038T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-152143704-A-G
• chr6-152143704-A-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.25038T>C​(p.Arg8346Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,613,882 control chromosomes in the GnomAD database, including 275,698 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30299 hom., cov: 32)
  • Exomes 𝑓: 0.58 (245399 hom.)
• Consequence: SYNE1 NM_182961.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.583
• Publications: 26 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 6-152143704-A-G is Benign according to our data. Variant chr6-152143704-A-G is described in ClinVar as Benign. ClinVar VariationId is 130430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.583 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.746 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.25038T>C	p.Arg8346Arg	synonymous	Exon 138 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.1572T>C	p.Arg524Arg	synonymous	Exon 10 of 18	NP_001334631.1	F8WAI0
	SYNE1	NM_033071.5		c.24894T>C	p.Arg8298Arg	synonymous	Exon 138 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.25038T>C	p.Arg8346Arg	synonymous	Exon 138 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.1572T>C	p.Arg524Arg	synonymous	Exon 10 of 18	ENSP00000346701.4	F8WAI0
	SYNE1	ENST00000423061.6	TSL:1	c.24894T>C	p.Arg8298Arg	synonymous	Exon 138 of 146	ENSP00000396024.1	A0A0C4DG40

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94736 AN: 151914 Hom.: 30249 Cov.: 32

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.698

Gnomad SAS AF: 0.684

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.637

GnomAD2 exomes AF: 0.611 AC: 153614 AN: 251476 AF XY: 0.607

Gnomad AFR exome AF: 0.758

Gnomad AMR exome AF: 0.715

Gnomad ASJ exome AF: 0.569

Gnomad EAS exome AF: 0.693

Gnomad FIN exome AF: 0.486

Gnomad NFE exome AF: 0.552

Gnomad OTH exome AF: 0.584

GnomAD4 exome AF: 0.576 AC: 842418 AN: 1461848 Hom.: 245399 Cov.: 61 AF XY: 0.578 AC XY: 420431 AN XY: 727234

African (AFR) AF: 0.756 AC: 25325 AN: 33480

American (AMR) AF: 0.710 AC: 31769 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 14837 AN: 26136

East Asian (EAS) AF: 0.713 AC: 28303 AN: 39698

South Asian (SAS) AF: 0.691 AC: 59584 AN: 86258

European-Finnish (FIN) AF: 0.495 AC: 26459 AN: 53418

Middle Eastern (MID) AF: 0.585 AC: 3372 AN: 5768

European-Non Finnish (NFE) AF: 0.555 AC: 617065 AN: 1111972

Other (OTH) AF: 0.591 AC: 35704 AN: 60394

GnomAD4 genome AF: 0.624 AC: 94853 AN: 152034 Hom.: 30299 Cov.: 32 AF XY: 0.624 AC XY: 46379 AN XY: 74288

African (AFR) AF: 0.753 AC: 31250 AN: 41480

American (AMR) AF: 0.673 AC: 10279 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1979 AN: 3470

East Asian (EAS) AF: 0.698 AC: 3606 AN: 5168

South Asian (SAS) AF: 0.683 AC: 3290 AN: 4820

European-Finnish (FIN) AF: 0.482 AC: 5069 AN: 10524

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.550 AC: 37403 AN: 67972

Other (OTH) AF: 0.639 AC: 1353 AN: 2116

Alfa AF: 0.584 Hom.: 114049

Bravo AF: 0.643

Asia WGS AF: 0.697 AC: 2424 AN: 3478

EpiCase AF: 0.551

EpiControl AF: 0.550

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
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.8
DANN	Benign	0.52
PhyloP100		0.58
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: rs2256135; hg19: chr6-152464839; COSMIC: COSV54938379; COSMIC: COSV54938379;