rs3829767

Variant names:

• chr14-64052737-A-G
• rs3829767
• NM_182914.3:c.8824A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-64052737-A-G
• chr14-64052737-A-C
• chr14-64052737-A-T

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.8824A>G​(p.Ile2942Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.838 in 1,613,072 control chromosomes in the GnomAD database, including 575,689 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2942T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.72 (42642 hom., cov: 33)
  • Exomes 𝑓: 0.85 (533047 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.838
• Publications: 35 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
• left ventricular noncompaction

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Emery-Dreifuss muscular dystrophy 5, autosomal dominant

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.3268174E-7).
• BP6: Variant 14-64052737-A-G is Benign according to our data. Variant chr14-64052737-A-G is described in ClinVar as Benign. ClinVar VariationId is 130516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.863 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.8824A>G	p.Ile2942Val	missense	Exon 48 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.8824A>G	p.Ile2942Val	missense	Exon 48 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.8824A>G	p.Ile2942Val	missense	Exon 48 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.8824A>G	p.Ile2942Val	missense	Exon 48 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000358025.7	TSL:5	c.8824A>G	p.Ile2942Val	missense	Exon 48 of 116	ENSP00000350719.3	Q8WXH0-2

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109486 AN: 152072 Hom.: 42642 Cov.: 33

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.890

Gnomad AMR AF: 0.776

Gnomad ASJ AF: 0.754

Gnomad EAS AF: 0.794

Gnomad SAS AF: 0.781

Gnomad FIN AF: 0.856

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.869

Gnomad OTH AF: 0.744

GnomAD2 exomes AF: 0.808 AC: 200783 AN: 248394 AF XY: 0.816

Gnomad AFR exome AF: 0.380

Gnomad AMR exome AF: 0.819

Gnomad ASJ exome AF: 0.742

Gnomad EAS exome AF: 0.787

Gnomad FIN exome AF: 0.864

Gnomad NFE exome AF: 0.867

Gnomad OTH exome AF: 0.809

GnomAD4 exome AF: 0.850 AC: 1241503 AN: 1460882 Hom.: 533047 Cov.: 58 AF XY: 0.849 AC XY: 617014 AN XY: 726626

African (AFR) AF: 0.364 AC: 12162 AN: 33402

American (AMR) AF: 0.813 AC: 36272 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 19402 AN: 26122

East Asian (EAS) AF: 0.778 AC: 30856 AN: 39684

South Asian (SAS) AF: 0.796 AC: 68540 AN: 86140

European-Finnish (FIN) AF: 0.867 AC: 46303 AN: 53388

Middle Eastern (MID) AF: 0.804 AC: 4635 AN: 5764

European-Non Finnish (NFE) AF: 0.876 AC: 974084 AN: 1111428

Other (OTH) AF: 0.816 AC: 49249 AN: 60352

GnomAD4 genome AF: 0.719 AC: 109498 AN: 152190 Hom.: 42642 Cov.: 33 AF XY: 0.721 AC XY: 53637 AN XY: 74396

African (AFR) AF: 0.393 AC: 16313 AN: 41470

American (AMR) AF: 0.776 AC: 11867 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.754 AC: 2612 AN: 3466

East Asian (EAS) AF: 0.793 AC: 4115 AN: 5186

South Asian (SAS) AF: 0.783 AC: 3778 AN: 4828

European-Finnish (FIN) AF: 0.856 AC: 9077 AN: 10600

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.869 AC: 59139 AN: 68032

Other (OTH) AF: 0.740 AC: 1565 AN: 2114

Alfa AF: 0.820 Hom.: 239409

Bravo AF: 0.700

TwinsUK AF: 0.879 AC: 3260

ALSPAC AF: 0.869 AC: 3351

ESP6500AA AF: 0.413 AC: 1538

ESP6500EA AF: 0.864 AC: 7070

ExAC AF: 0.802 AC: 96851

Asia WGS AF: 0.753 AC: 2618 AN: 3478

EpiCase AF: 0.868

EpiControl AF: 0.861

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.28
DANN	Benign	0.41
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	8.3e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.84
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.054
Sift	Benign	0.089	T
Sift4G	Benign	0.17	T
Polyphen		0.0020	B
Vest4		0.086
MPC		0.043
ClinPred		0.011	T
GERP RS		-7.9
Varity_R		0.024
gMVP		0.036
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3829767; hg19: chr14-64519455; COSMIC: COSV107421876; COSMIC: COSV107421876;