chr14-64190199-C-A

Variant names:

• chr14-64190199-C-A
• rs150002885
• NM_182914.3:c.18000C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_182914.3(SYNE2):​c.18000C>A​(p.Asn6000Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N6000N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.480

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]

ESR2 (HGNC:3468): (estrogen receptor 2) This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28930873).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000131 (20/152164) while in subpopulation NFE AF = 0.00025 (17/68008). AF 95% confidence interval is 0.000159. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.18000C>A	p.Asn6000Lys	missense_variant	Exon 99 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.18000C>A	p.Asn6000Lys	missense_variant	Exon 99 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000135 AC: 34 AN: 251440 AF XY: 0.000140

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1461886 Hom.: 0 Cov.: 34 AF XY: 0.000160 AC XY: 116 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33480

Gnomad4 AMR exome AF: 0.0000671 AC: 3 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26134

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39698

Gnomad4 SAS exome AF: 0.0000927 AC: 8 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53418

Gnomad4 NFE exome AF: 0.000198 AC: 220 AN: 1112010

Gnomad4 Remaining exome AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74390

Gnomad4 AFR AF: 0.0000482 AC: 0.0000481812 AN: 0.0000481812

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000208 AC: 0.000207641 AN: 0.000207641

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000250 AC: 0.000249971 AN: 0.000249971

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000120 Hom.: 0

Bravo AF: 0.000117

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.18000C>A (p.N6000K) alteration is located in exon 99 (coding exon 98) of the SYNE2 gene. This alteration results from a C to A substitution at nucleotide position 18000, causing the asparagine (N) at amino acid position 6000 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 6000 of the SYNE2 protein (p.Asn6000Lys). This variant is present in population databases (rs150002885, gnomAD 0.02%). 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: 568138). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	0.34
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	3.2
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	.;T;T;T;T
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	2.0	M;.;M;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.2	D;.;D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.026	D;.;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.50
MutPred		0.53		Loss of ubiquitination at K5995 (P = 0.0272);.;Loss of ubiquitination at K5995 (P = 0.0272);.;.;
MVP		0.47
MPC		0.31
ClinPred		0.64	D
GERP RS		-1.9
Varity_R		0.22
gMVP		0.70
Mutation Taster		=52/48	polymorphism

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: rs150002885; hg19: chr14-64656917;