6-152201677-T-G

Variant names:

• chr6-152201677-T-G
• rs2673776
• NM_182961.4:c.23145+147A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_182961.4(SYNE1):​c.23145+147A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 1,103,282 control chromosomes in the GnomAD database, including 185,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.58 (26078 hom., cov: 31)
  • Exomes 𝑓: 0.58 (159530 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.13
• Publications: 8 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-152201677-T-G is Benign according to our data. Variant chr6-152201677-T-G is described in ClinVar as [Benign]. Clinvar id is 670211.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.23145+147A>C		intron_variant	Intron 127 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.23145+147A>C		intron_variant	Intron 127 of 145	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88537 AN: 151838 Hom.: 26042 Cov.: 31

Gnomad AFR AF: 0.584

Gnomad AMI AF: 0.574

Gnomad AMR AF: 0.665

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.644

Gnomad SAS AF: 0.585

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.612

GnomAD4 exome AF: 0.576 AC: 547740 AN: 951326 Hom.: 159530 AF XY: 0.576 AC XY: 281150 AN XY: 488386

African (AFR) AF: 0.587 AC: 13751 AN: 23432

American (AMR) AF: 0.676 AC: 25281 AN: 37376

Ashkenazi Jewish (ASJ) AF: 0.594 AC: 12922 AN: 21764

East Asian (EAS) AF: 0.644 AC: 23586 AN: 36610

South Asian (SAS) AF: 0.566 AC: 40319 AN: 71208

European-Finnish (FIN) AF: 0.478 AC: 21651 AN: 45306

Middle Eastern (MID) AF: 0.604 AC: 2874 AN: 4760

European-Non Finnish (NFE) AF: 0.572 AC: 381755 AN: 667334

Other (OTH) AF: 0.588 AC: 25601 AN: 43536

GnomAD4 genome AF: 0.583 AC: 88637 AN: 151956 Hom.: 26078 Cov.: 31 AF XY: 0.579 AC XY: 42992 AN XY: 74288

African (AFR) AF: 0.585 AC: 24217 AN: 41424

American (AMR) AF: 0.666 AC: 10166 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2027 AN: 3466

East Asian (EAS) AF: 0.644 AC: 3321 AN: 5160

South Asian (SAS) AF: 0.586 AC: 2826 AN: 4820

European-Finnish (FIN) AF: 0.450 AC: 4751 AN: 10558

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.579 AC: 39324 AN: 67940

Other (OTH) AF: 0.615 AC: 1298 AN: 2112

Alfa AF: 0.587 Hom.: 87775

Bravo AF: 0.600

Asia WGS AF: 0.608 AC: 2114 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.32
DANN	Benign	0.50
PhyloP100		-1.1
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: rs2673776; hg19: chr6-152522812; COSMIC: COSV54945498;