14-64001936-T-C

Variant names:

• chr14-64001936-T-C
• rs201166748
• NM_182914.3:c.3641T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182914.3(SYNE2):​c.3641T>C​(p.Met1214Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1214K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.65
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2144849).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.3641T>C	p.Met1214Thr	missense splice_region	Exon 29 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.3641T>C	p.Met1214Thr	missense splice_region	Exon 29 of 115	NP_055995.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.3641T>C	p.Met1214Thr	missense splice_region	Exon 29 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.3641T>C	p.Met1214Thr	missense splice_region	Exon 29 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000358025.7	TSL:5	c.3641T>C	p.Met1214Thr	missense splice_region	Exon 29 of 116	ENSP00000350719.3	Q8WXH0-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15288

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: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	14
DANN	Benign	0.85
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.6
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.29	T
Polyphen		0.047	B
Vest4		0.55
MutPred		0.33		Gain of phosphorylation at M1214 (P = 0.0649)
MVP		0.52
MPC		0.090
ClinPred		0.26	T
GERP RS		5.2
Varity_R		0.53
gMVP		0.31
Mutation Taster		=91/9	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: rs201166748; hg19: chr14-64468654;