rs78110192

chr14-64074105-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.10835A>G(p.Gln3612Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00193 in 1,614,262 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (58 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.71

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=0.002723217).
• BP6: Variant 14-64074105-A-G is Benign according to our data. Variant chr14-64074105-A-G is described in ClinVar as [Benign]. Clinvar id is 130457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00307 (468/152392) while in subpopulation EAS AF= 0.0476 (247/5190). AF 95% confidence interval is 0.0427. There are 7 homozygotes in gnomad4. There are 258 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 468 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.10835A>G	p.Gln3612Arg	missense_variant	53/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.10835A>G	p.Gln3612Arg	missense_variant	53/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 468 AN: 152274 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000940

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0475

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00540 AC: 1348 AN: 249514 Hom.: 24 AF XY: 0.00448 AC XY: 606 AN XY: 135388

Gnomad AFR exome AF: 0.000775

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0483

Gnomad SAS exome AF: 0.000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00346

GnomAD4 exome AF: 0.00182 AC: 2654 AN: 1461870 Hom.: 58 Cov.: 32 AF XY: 0.00166 AC XY: 1205 AN XY: 727236

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.0140

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0441

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00311

GnomAD4 genome AF: 0.00307 AC: 468 AN: 152392 Hom.: 7 Cov.: 33 AF XY: 0.00346 AC XY: 258 AN XY: 74522

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0476

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00225 Hom.: 11

Bravo AF: 0.00447

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000808 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00473 AC: 571

Asia WGS AF: 0.0140 AC: 47 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 14, 2015	- -
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:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	18
Dann	Benign	0.97
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.79	T;T;T;T;T
MetaRNN	Benign	0.0027	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;.;M;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.6	N;.;N;N;N
REVEL	Benign	0.039
Sift	Uncertain	0.016	D;.;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		0.59	P;.;B;.;.
Vest4		0.21
MVP		0.44
MPC		0.15
ClinPred		0.027	T
GERP RS		4.1
Varity_R		0.083
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: rs78110192; hg19: chr14-64540823;