rs1890908

Variant names:

• chr14-64052317-A-G
• rs1890908
• NM_182914.3:c.8404A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-64052317-A-G
• chr14-64052317-A-C
• chr14-64052317-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.8404A>G​(p.Ser2802Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.927 in 1,614,086 control chromosomes in the GnomAD database, including 694,149 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. S2802N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.91 (63034 hom., cov: 32)
  • Exomes 𝑓: 0.93 (631115 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.59
• Publications: 41 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=9.721277E-7).
• BP6: Variant 14-64052317-A-G is Benign according to our data. Variant chr14-64052317-A-G is described in ClinVar as Benign. ClinVar VariationId is 130513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.934 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.8404A>G	p.Ser2802Gly	missense	Exon 48 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.8404A>G	p.Ser2802Gly	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.8404A>G	p.Ser2802Gly	missense	Exon 48 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.8404A>G	p.Ser2802Gly	missense	Exon 48 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000358025.7	TSL:5	c.8404A>G	p.Ser2802Gly	missense	Exon 48 of 116	ENSP00000350719.3	Q8WXH0-2

Frequencies

GnomAD3 genomes AF: 0.909 AC: 138301 AN: 152120 Hom.: 62983 Cov.: 32

Gnomad AFR AF: 0.868

Gnomad AMI AF: 0.995

Gnomad AMR AF: 0.918

Gnomad ASJ AF: 0.827

Gnomad EAS AF: 0.860

Gnomad SAS AF: 0.814

Gnomad FIN AF: 0.943

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.940

Gnomad OTH AF: 0.904

GnomAD2 exomes AF: 0.908 AC: 226629 AN: 249470 AF XY: 0.905

Gnomad AFR exome AF: 0.868

Gnomad AMR exome AF: 0.951

Gnomad ASJ exome AF: 0.820

Gnomad EAS exome AF: 0.844

Gnomad FIN exome AF: 0.943

Gnomad NFE exome AF: 0.937

Gnomad OTH exome AF: 0.899

GnomAD4 exome AF: 0.928 AC: 1357122 AN: 1461848 Hom.: 631115 Cov.: 71 AF XY: 0.925 AC XY: 672636 AN XY: 727228

African (AFR) AF: 0.864 AC: 28930 AN: 33480

American (AMR) AF: 0.947 AC: 42346 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 21293 AN: 26134

East Asian (EAS) AF: 0.867 AC: 34418 AN: 39698

South Asian (SAS) AF: 0.827 AC: 71342 AN: 86254

European-Finnish (FIN) AF: 0.942 AC: 50337 AN: 53416

Middle Eastern (MID) AF: 0.896 AC: 5168 AN: 5768

European-Non Finnish (NFE) AF: 0.943 AC: 1048328 AN: 1111986

Other (OTH) AF: 0.910 AC: 54960 AN: 60392

GnomAD4 genome AF: 0.909 AC: 138411 AN: 152238 Hom.: 63034 Cov.: 32 AF XY: 0.907 AC XY: 67524 AN XY: 74440

African (AFR) AF: 0.869 AC: 36065 AN: 41520

American (AMR) AF: 0.918 AC: 14042 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.827 AC: 2872 AN: 3472

East Asian (EAS) AF: 0.860 AC: 4457 AN: 5182

South Asian (SAS) AF: 0.814 AC: 3922 AN: 4816

European-Finnish (FIN) AF: 0.943 AC: 10013 AN: 10614

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.940 AC: 63967 AN: 68026

Other (OTH) AF: 0.903 AC: 1906 AN: 2110

Alfa AF: 0.924 Hom.: 313622

Bravo AF: 0.909

TwinsUK AF: 0.943 AC: 3497

ALSPAC AF: 0.937 AC: 3611

ESP6500AA AF: 0.870 AC: 3264

ESP6500EA AF: 0.932 AC: 7643

ExAC AF: 0.907 AC: 109514

Asia WGS AF: 0.844 AC: 2935 AN: 3478

EpiCase AF: 0.933

EpiControl AF: 0.929

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (4)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.016
DANN	Benign	0.60
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	9.7e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		-1.6
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.022
Sift	Benign	0.36	T
Sift4G	Benign	0.061	T
Polyphen		0.058	B
Vest4		0.028
MPC		0.053
ClinPred		0.0057	T
GERP RS		-6.9
Varity_R		0.034
gMVP		0.059
Mutation Taster		=299/1	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: rs1890908; hg19: chr14-64519035; COSMIC: COSV107421875; COSMIC: COSV107421875;