rs200447122

Positions:

• chr14-64051607-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_182914.3(SYNE2):​c.7694C>T​(p.Ala2565Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A2565A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.311

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.046861857).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000274 (40/1461460) while in subpopulation AFR AF= 0.0000299 (1/33394). AF 95% confidence interval is 0.0000118. There are 0 homozygotes in gnomad4_exome. There are 18 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.7694C>T	p.Ala2565Val	missense_variant	48/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.7694C>T	p.Ala2565Val	missense_variant	48/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000482 AC: 12 AN: 248978 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135162

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461460 Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18 AN XY: 727062

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000651

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000319 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000246 AC: 2

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 21, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 582586). This variant has not been reported in the literature in individuals affected with SYNE2-related conditions. This variant is present in population databases (rs200447122, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2565 of the SYNE2 protein (p.Ala2565Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.0
DANN	Benign	0.69
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.047	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.;L;.
MutationTaster	Benign	0.94	D;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.94	N;.;N;N
REVEL	Benign	0.0060
Sift	Benign	0.41	T;.;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.42	B;.;B;.
Vest4		0.13
MVP		0.35
MPC		0.050
ClinPred		0.054	T
GERP RS		2.9
Varity_R		0.017
gMVP		0.030

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: rs200447122; hg19: chr14-64518325;