rs3818110

Variant names:

• chr6-152139926-G-A
• rs3818110
• NM_182961.4:c.25458+24C>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.25458+24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,610,822 control chromosomes in the GnomAD database, including 128,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14404 hom., cov: 31)
  • Exomes 𝑓: 0.39 (114285 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.287
• Publications: 7 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 (BayesDel_noAF=-0.9).
• BP6: Variant 6-152139926-G-A is Benign according to our data. Variant chr6-152139926-G-A is described in ClinVar as Benign. ClinVar VariationId is 262193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.519 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.25458+24C>T		intron	N/A	NP_892006.3
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.1992+24C>T		intron	N/A	NP_001334631.1
	SYNE1	NM_033071.5		c.25314+24C>T		intron	N/A	NP_149062.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.25458+24C>T		intron	N/A	ENSP00000356224.5
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.1992+24C>T		intron	N/A	ENSP00000346701.4
	SYNE1	ENST00000423061.6	TSL:1	c.25314+24C>T		intron	N/A	ENSP00000396024.1

Frequencies

GnomAD3 genomes AF: 0.429 AC: 64863 AN: 151290 Hom.: 14403 Cov.: 31

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.468

GnomAD2 exomes AF: 0.408 AC: 101697 AN: 249532 AF XY: 0.404

Gnomad AFR exome AF: 0.529

Gnomad AMR exome AF: 0.532

Gnomad ASJ exome AF: 0.504

Gnomad EAS exome AF: 0.299

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.379

Gnomad OTH exome AF: 0.423

GnomAD4 exome AF: 0.392 AC: 571844 AN: 1459412 Hom.: 114285 Cov.: 35 AF XY: 0.393 AC XY: 285575 AN XY: 726014

African (AFR) AF: 0.524 AC: 17524 AN: 33416

American (AMR) AF: 0.532 AC: 23769 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 13299 AN: 26128

East Asian (EAS) AF: 0.308 AC: 12240 AN: 39684

South Asian (SAS) AF: 0.450 AC: 38745 AN: 86148

European-Finnish (FIN) AF: 0.249 AC: 13300 AN: 53356

Middle Eastern (MID) AF: 0.489 AC: 2206 AN: 4514

European-Non Finnish (NFE) AF: 0.384 AC: 426272 AN: 1111318

Other (OTH) AF: 0.407 AC: 24489 AN: 60198

GnomAD4 genome AF: 0.429 AC: 64914 AN: 151410 Hom.: 14404 Cov.: 31 AF XY: 0.425 AC XY: 31449 AN XY: 74000

African (AFR) AF: 0.525 AC: 21663 AN: 41244

American (AMR) AF: 0.498 AC: 7588 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1739 AN: 3468

East Asian (EAS) AF: 0.309 AC: 1579 AN: 5110

South Asian (SAS) AF: 0.437 AC: 2093 AN: 4788

European-Finnish (FIN) AF: 0.245 AC: 2581 AN: 10542

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26224 AN: 67738

Other (OTH) AF: 0.467 AC: 980 AN: 2100

Alfa AF: 0.402 Hom.: 5978

Bravo AF: 0.458

Asia WGS AF: 0.363 AC: 1260 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.90
PhyloP100		-0.29
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: rs3818110; hg19: chr6-152461061; COSMIC: COSV54896481;