rs2348080

Variant names:

• chr6-152151525-T-A
• rs2348080
• NM_182961.4:c.24450+28A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_182961.4(SYNE1):​c.24450+28A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0406 in 1,613,058 control chromosomes in the GnomAD database, including 1,530 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.043 (171 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1359 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.470
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-152151525-T-A is Benign according to our data. Variant chr6-152151525-T-A is described in ClinVar as Benign. ClinVar VariationId is 262189.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0429 (6536/152242) while in subpopulation AMR AF = 0.0505 (772/15300). AF 95% confidence interval is 0.0475. There are 171 homozygotes in GnomAd4. There are 3183 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 171 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.24450+28A>T		intron_variant	Intron 135 of 145	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2	c.915+28A>T		intron_variant	Intron 6 of 17	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.24450+28A>T		intron_variant	Intron 135 of 145	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000354674.5	c.915+28A>T		intron_variant	Intron 6 of 17	5	NM_001347702.2	ENSP00000346701.4

Frequencies

GnomAD3 genomes AF: 0.0428 AC: 6516 AN: 152124 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.0461

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0507

Gnomad ASJ AF: 0.0926

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.0428

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0411

Gnomad OTH AF: 0.0578

GnomAD2 exomes AF: 0.0383 AC: 9565 AN: 249744 AF XY: 0.0378

Gnomad AFR exome AF: 0.0468

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.0882

Gnomad EAS exome AF: 0.000817

Gnomad FIN exome AF: 0.0430

Gnomad NFE exome AF: 0.0440

Gnomad OTH exome AF: 0.0478

GnomAD4 exome AF: 0.0403 AC: 58928 AN: 1460816 Hom.: 1359 Cov.: 31 AF XY: 0.0398 AC XY: 28919 AN XY: 726644

African (AFR) AF: 0.0460 AC: 1540 AN: 33452

American (AMR) AF: 0.0345 AC: 1542 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0933 AC: 2437 AN: 26120

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39698

South Asian (SAS) AF: 0.0189 AC: 1629 AN: 85990

European-Finnish (FIN) AF: 0.0438 AC: 2330 AN: 53230

Middle Eastern (MID) AF: 0.0535 AC: 307 AN: 5736

European-Non Finnish (NFE) AF: 0.0417 AC: 46357 AN: 1111562

Other (OTH) AF: 0.0459 AC: 2773 AN: 60368

GnomAD4 genome AF: 0.0429 AC: 6536 AN: 152242 Hom.: 171 Cov.: 32 AF XY: 0.0428 AC XY: 3183 AN XY: 74456

African (AFR) AF: 0.0463 AC: 1923 AN: 41530

American (AMR) AF: 0.0505 AC: 772 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0926 AC: 321 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4826

European-Finnish (FIN) AF: 0.0428 AC: 454 AN: 10610

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0411 AC: 2792 AN: 68006

Other (OTH) AF: 0.0610 AC: 129 AN: 2114

Alfa AF: 0.0498 Hom.: 37

Bravo AF: 0.0433

Asia WGS AF: 0.0360 AC: 124 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.2
DANN	Benign	0.34
PhyloP100		0.47
PromoterAI		0.0045	Neutral
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: rs2348080; hg19: chr6-152472660;