14-64074030-C-T

Variant names:

• chr14-64074030-C-T
• rs748430621
• NM_182914.3:c.10760C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_182914.3(SYNE2):​c.10760C>T​(p.Ser3587Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000762 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. S3587C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.10
• Publications: 1 publications found

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]

SYNE2 Gene-Disease associations (from GenCC):

• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Emery-Dreifuss muscular dystrophy 5, autosomal dominant

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
• left ventricular noncompaction

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02136767).
• BP6: Variant 14-64074030-C-T is Benign according to our data. Variant chr14-64074030-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 448621.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000788 (12/152202) while in subpopulation AMR AF = 0.000458 (7/15272). AF 95% confidence interval is 0.000215. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 12 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182914.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.10760C>T	p.Ser3587Phe	missense	Exon 53 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.10760C>T	p.Ser3587Phe	missense	Exon 53 of 115	NP_055995.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.10760C>T	p.Ser3587Phe	missense	Exon 53 of 116	ENSP00000450831.2
	SYNE2	ENST00000344113.8	TSL:1	c.10760C>T	p.Ser3587Phe	missense	Exon 53 of 115	ENSP00000341781.4
	SYNE2	ENST00000358025.7	TSL:5	c.10760C>T	p.Ser3587Phe	missense	Exon 53 of 116	ENSP00000350719.3

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000272 AC: 68 AN: 249542 AF XY: 0.000148

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000759 AC: 111 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.0000578 AC XY: 42 AN XY: 727236

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00145 AC: 65 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111984

Other (OTH) AF: 0.000116 AC: 7 AN: 60394

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74340

African (AFR) AF: 0.0000482 AC: 2 AN: 41452

American (AMR) AF: 0.000458 AC: 7 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000162

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Feb 09, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SYNE2-related disorder Benign:1

Apr 21, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.058	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.1
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.046
Sift	Benign	0.031	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.83	P
Vest4		0.28
MVP		0.51
MPC		0.28
ClinPred		0.082	T
GERP RS		2.2
Varity_R		0.059
gMVP		0.069
Mutation Taster		=281/19	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

Other links and lift over

dbSNP: rs748430621; hg19: chr14-64540748; COSMIC: COSV59944912; COSMIC: COSV59944912;