14-64055956-G-C

Variant names:

• chr14-64055956-G-C
• rs8010911
• NM_182914.3:c.9757G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182914.3(SYNE2):​c.9757G>C​(p.Asp3253His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.84 in 1,612,456 control chromosomes in the GnomAD database, including 577,480 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (43618 hom., cov: 32)
  • Exomes 𝑓: 0.85 (533862 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.89
• Publications: 38 publications found

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]

SYNE2 Gene-Disease associations (from GenCC):

• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Emery-Dreifuss muscular dystrophy 5, autosomal dominant

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
• left ventricular noncompaction

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.1142125E-7).
• BP6: Variant 14-64055956-G-C is Benign according to our data. Variant chr14-64055956-G-C is described in ClinVar as Benign. ClinVar VariationId is 130520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.9757G>C	p.Asp3253His	missense_variant	Exon 49 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.9757G>C	p.Asp3253His	missense_variant	Exon 49 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.736 AC: 111811 AN: 151994 Hom.: 43614 Cov.: 32

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.890

Gnomad AMR AF: 0.780

Gnomad ASJ AF: 0.753

Gnomad EAS AF: 0.794

Gnomad SAS AF: 0.781

Gnomad FIN AF: 0.857

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.869

Gnomad OTH AF: 0.757

GnomAD2 exomes AF: 0.812 AC: 201325 AN: 248000 AF XY: 0.818

Gnomad AFR exome AF: 0.438

Gnomad AMR exome AF: 0.821

Gnomad ASJ exome AF: 0.742

Gnomad EAS exome AF: 0.786

Gnomad FIN exome AF: 0.864

Gnomad NFE exome AF: 0.867

Gnomad OTH exome AF: 0.810

GnomAD4 exome AF: 0.851 AC: 1243314 AN: 1460344 Hom.: 533862 Cov.: 37 AF XY: 0.851 AC XY: 617875 AN XY: 726478

African (AFR) AF: 0.424 AC: 14189 AN: 33434

American (AMR) AF: 0.816 AC: 36416 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 19383 AN: 26102

East Asian (EAS) AF: 0.778 AC: 30849 AN: 39676

South Asian (SAS) AF: 0.796 AC: 68461 AN: 86040

European-Finnish (FIN) AF: 0.867 AC: 46297 AN: 53382

Middle Eastern (MID) AF: 0.807 AC: 4647 AN: 5760

European-Non Finnish (NFE) AF: 0.876 AC: 973587 AN: 1110964

Other (OTH) AF: 0.820 AC: 49485 AN: 60336

GnomAD4 genome AF: 0.735 AC: 111842 AN: 152112 Hom.: 43618 Cov.: 32 AF XY: 0.737 AC XY: 54784 AN XY: 74376

African (AFR) AF: 0.449 AC: 18627 AN: 41450

American (AMR) AF: 0.780 AC: 11916 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.753 AC: 2615 AN: 3472

East Asian (EAS) AF: 0.794 AC: 4106 AN: 5172

South Asian (SAS) AF: 0.782 AC: 3769 AN: 4818

European-Finnish (FIN) AF: 0.857 AC: 9075 AN: 10590

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.869 AC: 59114 AN: 68018

Other (OTH) AF: 0.754 AC: 1587 AN: 2106

Alfa AF: 0.819 Hom.: 16804

Bravo AF: 0.718

TwinsUK AF: 0.879 AC: 3259

ALSPAC AF: 0.871 AC: 3355

ESP6500AA AF: 0.474 AC: 1821

ESP6500EA AF: 0.864 AC: 7124

ExAC AF: 0.806 AC: 97406

Asia WGS AF: 0.758 AC: 2637 AN: 3478

EpiCase AF: 0.868

EpiControl AF: 0.861

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 14, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.036	.;T;T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T;T;T;T
MetaRNN	Benign	7.1e-7	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.;M;.
PhyloP100		2.9
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N;.;N;N
REVEL	Benign	0.076
Sift	Benign	0.11	T;.;T;T
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.34	B;.;B;.
Vest4		0.25
MPC		0.26
ClinPred		0.031	T
GERP RS		2.9
Varity_R		0.048
gMVP		0.18
Mutation Taster		=291/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs8010911; hg19: chr14-64522674; COSMIC: COSV59966013;