chr14-63909170-C-T

Variant names:

• chr14-63909170-C-T
• rs2275017
• NM_182914.3:c.22C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182914.3(SYNE2):​c.22C>T​(p.Pro8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000359 in 1,612,932 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00037 (4 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.422
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042003095).
• BP6: Variant 14-63909170-C-T is Benign according to our data. Variant chr14-63909170-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 313482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000257 (39/151886) while in subpopulation EAS AF = 0.0058 (30/5174). AF 95% confidence interval is 0.00417. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 39 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.22C>T	p.Pro8Ser	missense_variant	Exon 2 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.22C>T	p.Pro8Ser	missense_variant	Exon 2 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.000264 AC: 40 AN: 151768 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00578

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000526 AC: 131 AN: 249260 AF XY: 0.000510

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00551

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000370 AC: 540 AN: 1461046 Hom.: 4 Cov.: 29 AF XY: 0.000382 AC XY: 278 AN XY: 726918

African (AFR) AF: 0.0000598 AC: 2 AN: 33460

American (AMR) AF: 0.000403 AC: 18 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26126

East Asian (EAS) AF: 0.0118 AC: 468 AN: 39694

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111286

Other (OTH) AF: 0.000182 AC: 11 AN: 60360

GnomAD4 genome AF: 0.000257 AC: 39 AN: 151886 Hom.: 0 Cov.: 31 AF XY: 0.000310 AC XY: 23 AN XY: 74214

African (AFR) AF: 0.0000966 AC: 4 AN: 41410

American (AMR) AF: 0.0000657 AC: 1 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00580 AC: 30 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000307 Hom.: 0

Bravo AF: 0.000321

ExAC AF: 0.000654 AC: 79

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SYNE2-related disorder Benign:1

Oct 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.032	.;T;T;.;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.037	N
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.0042	T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.4	L;.;L;L;.
PhyloP100		0.42
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.9	N;.;N;D;N
REVEL	Benign	0.086
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Uncertain	0.016	D;D;D;T;D
Polyphen		0.30	B;.;B;B;.
Vest4		0.068
MVP		0.61
MPC		0.072
ClinPred		0.041	T
GERP RS		3.5
PromoterAI		-0.0094	Neutral
Varity_R		0.16
gMVP		0.21
Mutation Taster		=88/12	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: rs2275017; hg19: chr14-64375888;