rs57259697

chr14-64000640-A-Cchr14-64000640-A-G

Variant summary

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

The NM_182914.3(SYNE2):c.3559A>C(p.Ile1187Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00581 in 1,613,540 control chromosomes in the GnomAD database, including 487 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (245 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (242 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.82

Genes affected

SYNE2 (HGNC:17084): (spectrin repeat containing nuclear envelope protein 2) The protein encoded by this gene is a nuclear outer membrane protein that binds cytoplasmic F-actin. This binding tethers the nucleus to the cytoskeleton and aids in the maintenance of the structural integrity of the nucleus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016278625).
• BP6: Variant 14-64000640-A-C is Benign according to our data. Variant chr14-64000640-A-C is described in ClinVar as [Benign]. Clinvar id is 130495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64000640-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.3559A>C	p.Ile1187Leu	missense_variant	28/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.3559A>C	p.Ile1187Leu	missense_variant	28/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0300 AC: 4567 AN: 152176 Hom.: 242 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.00795 AC: 1981 AN: 249110 Hom.: 92 AF XY: 0.00604 AC XY: 817 AN XY: 135180

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.00607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000239

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00327 AC: 4778 AN: 1461246 Hom.: 242 Cov.: 31 AF XY: 0.00279 AC XY: 2028 AN XY: 726942

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.00618

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000360

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.00673

GnomAD4 genome AF: 0.0301 AC: 4589 AN: 152294 Hom.: 245 Cov.: 32 AF XY: 0.0287 AC XY: 2139 AN XY: 74466

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.00456 Hom.: 56

Bravo AF: 0.0348

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.101 AC: 365

ESP6500EA AF: 0.000369 AC: 3

ExAC AF: 0.00985 AC: 1189

Asia WGS AF: 0.00953 AC: 33 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 22, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Apr 07, 2016	- -

SYNE2-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2020

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.0030
Dann	Benign	0.67
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.38	T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.68	N;.;N;N
REVEL	Benign	0.11
Sift	Benign	0.27	T;.;T;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.18
MutPred		0.28		Loss of methylation at K1188 (P = 0.0537);Loss of methylation at K1188 (P = 0.0537);Loss of methylation at K1188 (P = 0.0537);Loss of methylation at K1188 (P = 0.0537);
MVP		0.092
MPC		0.047
ClinPred		0.0028	T
GERP RS		-12
Varity_R		0.037
gMVP		0.070

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs57259697; hg19: chr14-64467358;