14-64052737-A-G

Position:

• chr14-64052737-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.8824A>G​(p.Ile2942Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.838 in 1,613,072 control chromosomes in the GnomAD database, including 575,689 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (42642 hom., cov: 33)
  • Exomes 𝑓: 0.85 (533047 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.838

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=8.3268174E-7).
• BP6: Variant 14-64052737-A-G is Benign according to our data. Variant chr14-64052737-A-G is described in ClinVar as [Benign]. Clinvar id is 130516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64052737-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.863 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.8824A>G	p.Ile2942Val	missense_variant	48/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.8824A>G	p.Ile2942Val	missense_variant	48/116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109486 AN: 152072 Hom.: 42642 Cov.: 33

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.890

Gnomad AMR AF: 0.776

Gnomad ASJ AF: 0.754

Gnomad EAS AF: 0.794

Gnomad SAS AF: 0.781

Gnomad FIN AF: 0.856

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.869

Gnomad OTH AF: 0.744

GnomAD3 exomes AF: 0.808 AC: 200783 AN: 248394 Hom.: 82965 AF XY: 0.816 AC XY: 109949 AN XY: 134812

Gnomad AFR exome AF: 0.380

Gnomad AMR exome AF: 0.819

Gnomad ASJ exome AF: 0.742

Gnomad EAS exome AF: 0.787

Gnomad SAS exome AF: 0.790

Gnomad FIN exome AF: 0.864

Gnomad NFE exome AF: 0.867

Gnomad OTH exome AF: 0.809

GnomAD4 exome AF: 0.850 AC: 1241503 AN: 1460882 Hom.: 533047 Cov.: 58 AF XY: 0.849 AC XY: 617014 AN XY: 726626

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.813

Gnomad4 ASJ exome AF: 0.743

Gnomad4 EAS exome AF: 0.778

Gnomad4 SAS exome AF: 0.796

Gnomad4 FIN exome AF: 0.867

Gnomad4 NFE exome AF: 0.876

Gnomad4 OTH exome AF: 0.816

GnomAD4 genome AF: 0.719 AC: 109498 AN: 152190 Hom.: 42642 Cov.: 33 AF XY: 0.721 AC XY: 53637 AN XY: 74396

Gnomad4 AFR AF: 0.393

Gnomad4 AMR AF: 0.776

Gnomad4 ASJ AF: 0.754

Gnomad4 EAS AF: 0.793

Gnomad4 SAS AF: 0.783

Gnomad4 FIN AF: 0.856

Gnomad4 NFE AF: 0.869

Gnomad4 OTH AF: 0.740

Alfa AF: 0.834 Hom.: 134623

Bravo AF: 0.700

TwinsUK AF: 0.879 AC: 3260

ALSPAC AF: 0.869 AC: 3351

ESP6500AA AF: 0.413 AC: 1538

ESP6500EA AF: 0.864 AC: 7070

ExAC AF: 0.802 AC: 96851

Asia WGS AF: 0.753 AC: 2618 AN: 3478

EpiCase AF: 0.868

EpiControl AF: 0.861

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 15, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.28
DANN	Benign	0.41
DEOGEN2	Benign	0.017	.;T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.55	T;T;T;T
MetaRNN	Benign	8.3e-7	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;.;L;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.58	N;.;N;N
REVEL	Benign	0.054
Sift	Benign	0.089	T;.;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.0020	B;.;B;.
Vest4		0.086
MPC		0.043
ClinPred		0.011	T
GERP RS		-7.9
Varity_R		0.024
gMVP		0.036

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3829767; hg19: chr14-64519455;