rs201664645

Positions:

• chr6-152132172-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_182961.4(SYNE1):​c.26044G>C​(p.Gly8682Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000105 in 1,614,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 5.66

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SYNE1
• BP4: Computational evidence support a benign effect (MetaRNN=0.11900774).
• BS2: High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.26044G>C	p.Gly8682Arg	missense_variant	144/146	ENST00000367255.10
SYNE1	NM_001347702.2	c.2578G>C	p.Gly860Arg	missense_variant	16/18	ENST00000354674.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.26044G>C	p.Gly8682Arg	missense_variant	144/146	1	NM_182961.4	P1
SYNE1	ENST00000354674.5	c.2578G>C	p.Gly860Arg	missense_variant	16/18	5	NM_001347702.2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000258 AC: 65 AN: 251496 Hom.: 0 AF XY: 0.000294 AC XY: 40 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000917 AC: 134 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.000111 AC XY: 81 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74478

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.0000904 Hom.: 0

Bravo AF: 0.000397

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 13, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	SYNE1: PM2 -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 07, 2022

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 8634 of the SYNE1 protein (p.Gly8634Arg). This variant is present in population databases (rs201664645, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 448594). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;.;.;T;T;T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.8	D;.;D;D;D;D;D
REVEL	Benign	0.27
Sift	Benign	0.055	T;.;D;T;T;T;D
Sift4G	Uncertain	0.031	D;D;T;D;D;D;T
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.89
MutPred		0.23		Gain of helix (P = 0.0078);.;.;.;.;.;.;
MVP		0.80
MPC		0.65
ClinPred		0.22	T
GERP RS		5.8
Varity_R		0.27
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: rs201664645; hg19: chr6-152453307; COSMIC: COSV104541763; COSMIC: COSV104541763;