rs763218931

chr6-152301991-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_182961.4(SYNE1):c.17419A>G(p.Met5807Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.42

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 -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SYNE1
• BP4: Computational evidence support a benign effect (MetaRNN=0.047954947).
• BS2: High AC in GnomAdExome at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.17419A>G	p.Met5807Val	missense_variant	92/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.17419A>G	p.Met5807Val	missense_variant	92/146	1	NM_182961.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000437 AC: 11 AN: 251492 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 471008). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. This variant is present in population databases (rs763218931, gnomAD 0.04%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 5736 of the SYNE1 protein (p.Met5736Val). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 05, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	15
Dann	Benign	0.85
DEOGEN2	Benign	0.074	T;.;T;T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.048	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.42	N;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.43	N;.;N;N;N
REVEL	Benign	0.098
Sift	Benign	1.0	T;.;T;T;T
Sift4G	Benign	0.99	T;T;T;.;.
Polyphen		0.11	B;.;.;.;.
Vest4		0.13
MutPred		0.22		Loss of disorder (P = 0.0603);.;.;.;.;
MVP		0.34
MPC		0.14
ClinPred		0.061	T
GERP RS		4.8
Varity_R		0.41
gMVP		0.13

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs763218931; hg19: chr6-152623126;