rs142985368

Positions:

• chr6-152148194-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_182961.4(SYNE1):​c.24827C>G​(p.Ala8276Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000416 in 1,614,082 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (3 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6 O:1
• Conservation: PhyloP100: 9.57

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SYNE1
• BP4: Computational evidence support a benign effect (MetaRNN=0.010953575).
• BP6: Variant 6-152148194-G-C is Benign according to our data. Variant chr6-152148194-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194305.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, not_provided=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.24827C>G	p.Ala8276Gly	missense_variant	137/146	ENST00000367255.10
SYNE1	NM_001347702.2	c.1292C>G	p.Ala431Gly	missense_variant	8/18	ENST00000354674.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.24827C>G	p.Ala8276Gly	missense_variant	137/146	1	NM_182961.4	P1
SYNE1	ENST00000354674.5	c.1292C>G	p.Ala431Gly	missense_variant	8/18	5	NM_001347702.2

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000827 AC: 208 AN: 251370 Hom.: 1 AF XY: 0.000817 AC XY: 111 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000408 AC: 596 AN: 1461888 Hom.: 3 Cov.: 36 AF XY: 0.000425 AC XY: 309 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.0152

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000971

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000605 AC XY: 45 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.0158

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.00122 Hom.: 1

Bravo AF: 0.000620

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000601 AC: 73

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 21, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SYNE1: BS1 -

Autosomal recessive ataxia, Beauce type Uncertain:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Uncertain significance and reported on 07-09-2015 by Lab or GTR ID 500060. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 28, 2017

- -

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;.;T;T;T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;T;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Pathogenic	3.0	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.5	D;.;D;D;D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.014	D;.;T;D;D;D;T
Sift4G	Uncertain	0.028	D;D;T;T;D;T;T
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.42
MVP		0.59
MPC		0.55
ClinPred		0.14	T
GERP RS		5.3
Varity_R		0.43
gMVP		0.52

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs142985368; hg19: chr6-152469329; COSMIC: COSV55046068; COSMIC: COSV55046068;