rs4902264

Positions:

• chr14-64024977-T-C
• chr14-64024977-T-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.5906T>C​(p.Met1969Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.848 in 1,613,774 control chromosomes in the GnomAD database, including 589,138 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1969I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.73 (43964 hom., cov: 32)
  • Exomes 𝑓: 0.86 (545174 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0370

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=7.5595824E-7).
• BP6: Variant 14-64024977-T-C is Benign according to our data. Variant chr14-64024977-T-C is described in ClinVar as [Benign]. Clinvar id is 130501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64024977-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.5906T>C	p.Met1969Thr	missense_variant	40/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.5906T>C	p.Met1969Thr	missense_variant	40/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111623 AN: 152004 Hom.: 43963 Cov.: 32

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.884

Gnomad AMR AF: 0.776

Gnomad ASJ AF: 0.791

Gnomad EAS AF: 0.792

Gnomad SAS AF: 0.803

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.879

Gnomad OTH AF: 0.755

GnomAD3 exomes AF: 0.816 AC: 203604 AN: 249398 Hom.: 84839 AF XY: 0.825 AC XY: 111622 AN XY: 135318

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.803

Gnomad ASJ exome AF: 0.774

Gnomad EAS exome AF: 0.788

Gnomad SAS exome AF: 0.810

Gnomad FIN exome AF: 0.873

Gnomad NFE exome AF: 0.876

Gnomad OTH exome AF: 0.815

GnomAD4 exome AF: 0.860 AC: 1256367 AN: 1461654 Hom.: 545174 Cov.: 48 AF XY: 0.859 AC XY: 624734 AN XY: 727128

Gnomad4 AFR exome AF: 0.391

Gnomad4 AMR exome AF: 0.799

Gnomad4 ASJ exome AF: 0.777

Gnomad4 EAS exome AF: 0.777

Gnomad4 SAS exome AF: 0.813

Gnomad4 FIN exome AF: 0.876

Gnomad4 NFE exome AF: 0.886

Gnomad4 OTH exome AF: 0.826

GnomAD4 genome AF: 0.734 AC: 111639 AN: 152120 Hom.: 43964 Cov.: 32 AF XY: 0.735 AC XY: 54638 AN XY: 74374

Gnomad4 AFR AF: 0.423

Gnomad4 AMR AF: 0.776

Gnomad4 ASJ AF: 0.791

Gnomad4 EAS AF: 0.792

Gnomad4 SAS AF: 0.804

Gnomad4 FIN AF: 0.865

Gnomad4 NFE AF: 0.879

Gnomad4 OTH AF: 0.754

Alfa AF: 0.843 Hom.: 136607

Bravo AF: 0.712

TwinsUK AF: 0.883 AC: 3275

ALSPAC AF: 0.878 AC: 3383

ESP6500AA AF: 0.444 AC: 1642

ESP6500EA AF: 0.875 AC: 7155

ExAC AF: 0.811 AC: 98029

Asia WGS AF: 0.763 AC: 2655 AN: 3478

EpiCase AF: 0.875

EpiControl AF: 0.867

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	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 14, 2018	- -
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	0.12
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.60
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.44	T;T;T;T
MetaRNN	Benign	7.6e-7	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N;.;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.1	N;.;N;N
REVEL	Benign	0.035
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	0.091	T;D;T;D
Polyphen		0.0030	B;.;B;.
Vest4		0.13
MPC		0.053
ClinPred		0.0035	T
GERP RS		-1.3
Varity_R		0.035
gMVP		0.077

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: rs4902264; hg19: chr14-64491695;