NM_182914.3:c.1873C>T

Variant names:

• chr14-63982666-C-T
• rs192061494
• NM_182914.3:c.1873C>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.1873C>T​(p.His625Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,613,832 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H625H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.60
• Publications: 2 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=0.005859375).
• BP6: Variant 14-63982666-C-T is Benign according to our data. Variant chr14-63982666-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 282409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000974 (148/152028) while in subpopulation AMR AF = 0.00308 (47/15262). AF 95% confidence interval is 0.00238. There are 0 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 148 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.1873C>T	p.His625Tyr	missense	Exon 17 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.1873C>T	p.His625Tyr	missense	Exon 17 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.1873C>T	p.His625Tyr	missense	Exon 17 of 116	ENSP00000450831.2
	SYNE2	ENST00000344113.8	TSL:1	c.1873C>T	p.His625Tyr	missense	Exon 17 of 115	ENSP00000341781.4
	SYNE2	ENST00000358025.7	TSL:5	c.1873C>T	p.His625Tyr	missense	Exon 17 of 116	ENSP00000350719.3

Frequencies

GnomAD3 genomes AF: 0.000981 AC: 149 AN: 151912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000285

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000946 AC: 236 AN: 249548 AF XY: 0.000879

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00138 AC: 2013 AN: 1461804 Hom.: 2 Cov.: 32 AF XY: 0.00127 AC XY: 926 AN XY: 727202

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.00114 AC: 51 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000651 AC: 17 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000580 AC: 31 AN: 53412

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00160 AC: 1783 AN: 1111958

Other (OTH) AF: 0.00189 AC: 114 AN: 60392

GnomAD4 genome AF: 0.000974 AC: 148 AN: 152028 Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74284

African (AFR) AF: 0.000458 AC: 19 AN: 41476

American (AMR) AF: 0.00308 AC: 47 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000285 AC: 3 AN: 10508

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68006

Other (OTH) AF: 0.00190 AC: 4 AN: 2104

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.00134

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.00217 AC: 18

ExAC AF: 0.000869 AC: 105

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00113

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.23
Sift	Benign	0.039	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.13	B
Vest4		0.34
MVP		0.35
MPC		0.055
ClinPred		0.024	T
GERP RS		4.1
Varity_R		0.18
gMVP		0.51
Mutation Taster		=277/23	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: rs192061494; hg19: chr14-64449384;