rs201858632

chr14-63998242-T-G

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.3267T>G(p.Phe1089Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.604

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=0.011279583).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000164 (25/152356) while in subpopulation AMR AF= 0.00144 (22/15304). AF 95% confidence interval is 0.000972. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.3267T>G	p.Phe1089Leu	missense_variant	26/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.3267T>G	p.Phe1089Leu	missense_variant	26/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

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: 0.0000120 AC: 3 AN: 249414 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135302

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461612 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74512

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

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: 0.0000564 Hom.: 0

Bravo AF: 0.000340

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 15, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1089 of the SYNE2 protein (p.Phe1089Leu). This variant is present in population databases (rs201858632, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SYNE2-related conditions. ClinVar contains an entry for this variant (Variation ID: 538331). 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 leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	1.3
Dann	Benign	0.61
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.55	T;T;T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.56	N;.;N;N
REVEL	Benign	0.025
Sift	Benign	0.21	T;.;T;T
Sift4G	Uncertain	0.040	D;D;D;D
Polyphen		0.0040	B;.;B;.
Vest4		0.085
MutPred		0.098		Loss of methylation at K1088 (P = 0.0405);Loss of methylation at K1088 (P = 0.0405);Loss of methylation at K1088 (P = 0.0405);Loss of methylation at K1088 (P = 0.0405);
MVP		0.17
MPC		0.055
ClinPred		0.021	T
GERP RS		-3.5
Varity_R		0.061
gMVP		0.10

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: rs201858632; hg19: chr14-64464960;