rs78191145

chr14-63983761-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182914.3(SYNE2):c.2026A>G(p.Lys676Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,613,084 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (8 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.37

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=0.0058240592).
• BP6: Variant 14-63983761-A-G is Benign according to our data. Variant chr14-63983761-A-G is described in ClinVar as [Benign]. Clinvar id is 130491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-63983761-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00553 (842/152310) while in subpopulation AFR AF= 0.0196 (815/41558). AF 95% confidence interval is 0.0185. There are 14 homozygotes in gnomad4. There are 409 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 838 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.2026A>G	p.Lys676Glu	missense_variant	18/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.2026A>G	p.Lys676Glu	missense_variant	18/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.00551 AC: 838 AN: 152192 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00146 AC: 365 AN: 249166 Hom.: 5 AF XY: 0.000998 AC XY: 135 AN XY: 135228

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.000638

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000608 AC: 888 AN: 1460774 Hom.: 8 Cov.: 30 AF XY: 0.000509 AC XY: 370 AN XY: 726748

Gnomad4 AFR exome AF: 0.0226

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00553 AC: 842 AN: 152310 Hom.: 14 Cov.: 32 AF XY: 0.00549 AC XY: 409 AN XY: 74474

Gnomad4 AFR AF: 0.0196

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00233 Hom.: 2

Bravo AF: 0.00653

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0237 AC: 85

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00187 AC: 226

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:2

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	Invitae	Jan 29, 2024	- -

not specified Benign:1

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. -

SYNE2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 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	0.096
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.57	T;T;T;T
MetaRNN	Benign	0.0058	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;.;M;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.98	N;.;N;N
REVEL	Benign	0.046
Sift	Uncertain	0.0090	D;.;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		0.87	P;.;P;.
Vest4		0.34
MVP		0.36
MPC		0.19
ClinPred		0.021	T
GERP RS		3.0
Varity_R		0.15
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs78191145; hg19: chr14-64450479; COSMIC: COSV59972047;