rs4902264

Variant names:

• chr14-64024977-T-C
• rs4902264
• NM_182914.3:c.5906T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-64024977-T-C
• chr14-64024977-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182914.3(SYNE2):​c.5906T>C​(p.Met1969Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.848 in 1,613,774 control chromosomes in the GnomAD database, including 589,138 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1969I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.73 (43964 hom., cov: 32)
  • Exomes 𝑓: 0.86 (545174 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0370
• Publications: 39 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=7.5595824E-7).
• BP6: Variant 14-64024977-T-C is Benign according to our data. Variant chr14-64024977-T-C is described in ClinVar as Benign. ClinVar VariationId is 130501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.873 is higher than 0.05.

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.5906T>C	p.Met1969Thr	missense	Exon 40 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.5906T>C	p.Met1969Thr	missense	Exon 40 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.5906T>C	p.Met1969Thr	missense	Exon 40 of 116	ENSP00000450831.2
	SYNE2	ENST00000344113.8	TSL:1	c.5906T>C	p.Met1969Thr	missense	Exon 40 of 115	ENSP00000341781.4
	SYNE2	ENST00000358025.7	TSL:5	c.5906T>C	p.Met1969Thr	missense	Exon 40 of 116	ENSP00000350719.3

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111623 AN: 152004 Hom.: 43963 Cov.: 32

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.884

Gnomad AMR AF: 0.776

Gnomad ASJ AF: 0.791

Gnomad EAS AF: 0.792

Gnomad SAS AF: 0.803

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.879

Gnomad OTH AF: 0.755

GnomAD2 exomes AF: 0.816 AC: 203604 AN: 249398 AF XY: 0.825

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.803

Gnomad ASJ exome AF: 0.774

Gnomad EAS exome AF: 0.788

Gnomad FIN exome AF: 0.873

Gnomad NFE exome AF: 0.876

Gnomad OTH exome AF: 0.815

GnomAD4 exome AF: 0.860 AC: 1256367 AN: 1461654 Hom.: 545174 Cov.: 48 AF XY: 0.859 AC XY: 624734 AN XY: 727128

African (AFR) AF: 0.391 AC: 13086 AN: 33466

American (AMR) AF: 0.799 AC: 35722 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.777 AC: 20306 AN: 26128

East Asian (EAS) AF: 0.777 AC: 30812 AN: 39664

South Asian (SAS) AF: 0.813 AC: 70128 AN: 86256

European-Finnish (FIN) AF: 0.876 AC: 46806 AN: 53418

Middle Eastern (MID) AF: 0.786 AC: 4528 AN: 5764

European-Non Finnish (NFE) AF: 0.886 AC: 985116 AN: 1111864

Other (OTH) AF: 0.826 AC: 49863 AN: 60386

GnomAD4 genome AF: 0.734 AC: 111639 AN: 152120 Hom.: 43964 Cov.: 32 AF XY: 0.735 AC XY: 54638 AN XY: 74374

African (AFR) AF: 0.423 AC: 17519 AN: 41464

American (AMR) AF: 0.776 AC: 11862 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.791 AC: 2746 AN: 3472

East Asian (EAS) AF: 0.792 AC: 4097 AN: 5172

South Asian (SAS) AF: 0.804 AC: 3881 AN: 4828

European-Finnish (FIN) AF: 0.865 AC: 9155 AN: 10586

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.879 AC: 59773 AN: 68004

Other (OTH) AF: 0.754 AC: 1587 AN: 2104

Alfa AF: 0.827 Hom.: 174991

Bravo AF: 0.712

TwinsUK AF: 0.883 AC: 3275

ALSPAC AF: 0.878 AC: 3383

ESP6500AA AF: 0.444 AC: 1642

ESP6500EA AF: 0.875 AC: 7155

ExAC AF: 0.811 AC: 98029

Asia WGS AF: 0.763 AC: 2655 AN: 3478

EpiCase AF: 0.875

EpiControl AF: 0.867

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (3)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.60
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	7.6e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.037
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.035
Sift	Benign	1.0	T
Sift4G	Benign	0.091	T
Polyphen		0.0030	B
Vest4		0.13
MPC		0.053
ClinPred		0.0035	T
GERP RS		-1.3
Varity_R		0.035
gMVP		0.077
Mutation Taster		=295/5	polymorphism (auto)

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: rs4902264; hg19: chr14-64491695; COSMIC: COSV107421873;