rs6932325

Positions:

• chr6-152352384-A-C
• chr6-152352384-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182961.4(SYNE1):​c.11254-31T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 1,599,144 control chromosomes in the GnomAD database, including 289,613 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.58 (25233 hom., cov: 30)
  • Exomes 𝑓: 0.60 (264380 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.349

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 0 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-152352384-A-C is Benign according to our data. Variant chr6-152352384-A-C is described in ClinVar as [Benign]. Clinvar id is 262153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.11254-31T>G		intron_variant		ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.11254-31T>G		intron_variant		1	NM_182961.4	P1
SYNE1	ENST00000423061.6	c.11209-31T>G		intron_variant		1
SYNE1	ENST00000471834.1	n.4392-31T>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.576 AC: 87102 AN: 151274 Hom.: 25216 Cov.: 30

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.591

GnomAD3 exomes AF: 0.583 AC: 142089 AN: 243540 Hom.: 41696 AF XY: 0.582 AC XY: 76647 AN XY: 131778

Gnomad AFR exome AF: 0.509

Gnomad AMR exome AF: 0.599

Gnomad ASJ exome AF: 0.644

Gnomad EAS exome AF: 0.603

Gnomad SAS exome AF: 0.523

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.603

Gnomad OTH exome AF: 0.586

GnomAD4 exome AF: 0.603 AC: 873439 AN: 1447762 Hom.: 264380 Cov.: 30 AF XY: 0.601 AC XY: 432844 AN XY: 720434

Gnomad4 AFR exome AF: 0.499

Gnomad4 AMR exome AF: 0.601

Gnomad4 ASJ exome AF: 0.647

Gnomad4 EAS exome AF: 0.639

Gnomad4 SAS exome AF: 0.523

Gnomad4 FIN exome AF: 0.545

Gnomad4 NFE exome AF: 0.614

Gnomad4 OTH exome AF: 0.596

GnomAD4 genome AF: 0.576 AC: 87161 AN: 151382 Hom.: 25233 Cov.: 30 AF XY: 0.572 AC XY: 42273 AN XY: 73910

Gnomad4 AFR AF: 0.512

Gnomad4 AMR AF: 0.613

Gnomad4 ASJ AF: 0.641

Gnomad4 EAS AF: 0.619

Gnomad4 SAS AF: 0.535

Gnomad4 FIN AF: 0.531

Gnomad4 NFE AF: 0.609

Gnomad4 OTH AF: 0.593

Alfa AF: 0.538 Hom.: 3386

Bravo AF: 0.580

Asia WGS AF: 0.594 AC: 2069 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Arthrogryposis multiplex congenita 3, myogenic type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Autosomal recessive ataxia, Beauce type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.90
DANN	Benign	0.29
BranchPoint Hunter		0.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6932325; hg19: chr6-152673519; COSMIC: COSV55004686;