rs190582637

Positions:

• chr14-64051811-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000555002.6(SYNE2):​c.7898A>G​(p.Asn2633Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,614,160 control chromosomes in the GnomAD database, including 47 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 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (45 hom.)
• Consequence: SYNE2 ENST00000555002.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0320

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=0.003028512).
• BP6: Variant 14-64051811-A-G is Benign according to our data. Variant chr14-64051811-A-G is described in ClinVar as [Benign]. Clinvar id is 183364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64051811-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00205 (312/152314) while in subpopulation SAS AF= 0.0145 (70/4828). AF 95% confidence interval is 0.0118. There are 2 homozygotes in gnomad4. There are 176 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 312 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.7898A>G	p.Asn2633Ser	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.7898A>G	p.Asn2633Ser	missense_variant	48/116	1	NM_182914.3	ENSP00000450831	P4

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 310 AN: 152196 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00363 AC: 905 AN: 249144 Hom.: 7 AF XY: 0.00458 AC XY: 619 AN XY: 135190

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00716

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0159

Gnomad FIN exome AF: 0.00186

Gnomad NFE exome AF: 0.00215

Gnomad OTH exome AF: 0.00347

GnomAD4 exome AF: 0.00255 AC: 3726 AN: 1461846 Hom.: 45 Cov.: 30 AF XY: 0.00305 AC XY: 2218 AN XY: 727222

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.00777

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0163

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.00151

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.00205 AC: 312 AN: 152314 Hom.: 2 Cov.: 32 AF XY: 0.00236 AC XY: 176 AN XY: 74488

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.00171

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00218 Hom.: 0

Bravo AF: 0.00184

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000519 AC: 2

ESP6500EA AF: 0.00229 AC: 19

ExAC AF: 0.00364 AC: 440

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00231

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 25, 2020	- -
Likely benign, no assertion criteria provided	research	Blueprint Genetics	Mar 02, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2015	- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.17
DANN	Benign	0.31
DEOGEN2	Benign	0.0045	.;T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.72	T;T;T;T
MetaRNN	Benign	0.0030	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.46	N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.50	N;.;N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	0.66	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.028
MVP		0.15
MPC		0.041
ClinPred		0.0022	T
GERP RS		-4.0
Varity_R		0.021
gMVP		0.011

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: rs190582637; hg19: chr14-64518529;