rs199996504

chr6-152325290-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_182961.4(SYNE1):c.15451G>A(p.Val5151Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000502 in 1,614,166 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V5151V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (11 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0170

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SYNE1
• BP4: Computational evidence support a benign effect (MetaRNN=0.007967234).
• BP6: Variant 6-152325290-C-T is Benign according to our data. Variant chr6-152325290-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 284630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152325290-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.15451G>A	p.Val5151Met	missense_variant	81/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.15451G>A	p.Val5151Met	missense_variant	81/146	1	NM_182961.4	P1
SYNE1	ENST00000423061.6	c.15238G>A	p.Val5080Met	missense_variant	80/146	1
SYNE1	ENST00000490135.6	n.2797G>A		non_coding_transcript_exon_variant	5/11	1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152168 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000998 AC: 251 AN: 251404 Hom.: 5 AF XY: 0.00138 AC XY: 188 AN XY: 135888

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00771

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000534 AC: 781 AN: 1461882 Hom.: 11 Cov.: 32 AF XY: 0.000770 AC XY: 560 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00767

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000674

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152284 Hom.: 1 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74472

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.00104 AC: 126

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 20, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2017	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

SYNE1: BP4, BS2 -

SYNE1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	8.1
Dann	Benign	0.71
DEOGEN2	Benign	0.074	T;.;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0080	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.040	N;.;N
REVEL	Benign	0.033
Sift	Benign	0.11	T;.;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.26
MutPred		0.32		Gain of MoRF binding (P = 0.1981);.;.;
MVP		0.27
MPC		0.14
ClinPred		0.022	T
GERP RS		3.7
Varity_R		0.061
gMVP		0.042

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199996504; hg19: chr6-152646425;