14-64053309-G-C

Position:

• chr14-64053309-G-C

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.9396G>C​(p.Lys3132Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,610,256 control chromosomes in the GnomAD database, including 25 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00086 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (23 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.201

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=0.0037957132).
• BP6: Variant 14-64053309-G-C is Benign according to our data. Variant chr14-64053309-G-C is described in ClinVar as [Benign]. Clinvar id is 313545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64053309-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00086 (131/152288) while in subpopulation SAS AF= 0.0237 (114/4816). AF 95% confidence interval is 0.0201. There are 2 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 131 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.9396G>C	p.Lys3132Asn	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.9396G>C	p.Lys3132Asn	missense_variant	48/116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152170 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0237

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00262 AC: 643 AN: 245788 Hom.: 7 AF XY: 0.00356 AC XY: 474 AN XY: 133198

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.0215

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.00129 AC: 1885 AN: 1457968 Hom.: 23 Cov.: 36 AF XY: 0.00187 AC XY: 1354 AN XY: 724982

Gnomad4 AFR exome AF: 0.000935

Gnomad4 AMR exome AF: 0.0000455

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0205

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152288 Hom.: 2 Cov.: 33 AF XY: 0.00118 AC XY: 88 AN XY: 74458

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0237

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000193

ExAC AF: 0.00303 AC: 366

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 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	Dec 04, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.0
DANN	Benign	0.85
DEOGEN2	Benign	0.029	.;T;T;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.62	T;T;T;T
MetaRNN	Benign	0.0038	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.;M;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N;.;N;N
REVEL	Benign	0.026
Sift	Benign	0.32	T;.;T;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.12
MutPred		0.19		Loss of ubiquitination at K3132 (P = 0.0141);.;Loss of ubiquitination at K3132 (P = 0.0141);.;
MVP		0.30
MPC		0.056
ClinPred		0.026	T
GERP RS		1.5
Varity_R		0.058
gMVP		0.13

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: rs566182360; hg19: chr14-64520027; COSMIC: COSV59964636; COSMIC: COSV59964636;