14-64056125-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_182914.3(SYNE2):c.9926A>T(p.His3309Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,613,844 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3309R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.13

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01112932).
• BP6: Variant 14-64056125-A-T is Benign according to our data. Variant chr14-64056125-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282107.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000382 (58/151994) while in subpopulation AFR AF= 0.00138 (57/41338). AF 95% confidence interval is 0.00109. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.9926A>T	p.His3309Leu	missense_variant	49/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.9926A>T	p.His3309Leu	missense_variant	49/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.000382 AC: 58 AN: 151994 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000962 AC: 24 AN: 249528 Hom.: 0 AF XY: 0.0000812 AC XY: 11 AN XY: 135390

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.0000499 AC: 73 AN: 1461850 Hom.: 0 Cov.: 54 AF XY: 0.0000413 AC XY: 30 AN XY: 727230

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.0000894

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000382 AC: 58 AN: 151994 Hom.: 0 Cov.: 30 AF XY: 0.000364 AC XY: 27 AN XY: 74222

Gnomad4 AFR AF: 0.00138

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000110 Hom.: 130678

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Aug 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 13, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 17, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	4.3
Dann	Benign	0.64
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.70	T;T;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.9	D;.;D;D
REVEL	Benign	0.032
Sift	Uncertain	0.013	D;.;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		0.020	B;.;B;.
Vest4		0.091
MVP		0.23
MPC		0.057
ClinPred		0.040	T
GERP RS		3.4
Varity_R		0.094
gMVP		0.11

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: rs8010699; hg19: chr14-64522843;