chr14-64000640-A-C

Variant names:

• chr14-64000640-A-C
• rs57259697
• NM_182914.3:c.3559A>C

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.3559A>C​(p.Ile1187Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00581 in 1,613,540 control chromosomes in the GnomAD database, including 487 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (245 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (242 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.82
• 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
• 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=0.0016278625).
• BP6: Variant 14-64000640-A-C is Benign according to our data. Variant chr14-64000640-A-C is described in ClinVar as Benign. ClinVar VariationId is 130495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 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.3559A>C	p.Ile1187Leu	missense	Exon 28 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.3559A>C	p.Ile1187Leu	missense	Exon 28 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.3559A>C	p.Ile1187Leu	missense	Exon 28 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.3559A>C	p.Ile1187Leu	missense	Exon 28 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000358025.7	TSL:5	c.3559A>C	p.Ile1187Leu	missense	Exon 28 of 116	ENSP00000350719.3	Q8WXH0-2

Frequencies

GnomAD3 genomes AF: 0.0300 AC: 4567 AN: 152176 Hom.: 242 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.00795 AC: 1981 AN: 249110 AF XY: 0.00604

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.00607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000239

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00327 AC: 4778 AN: 1461246 Hom.: 242 Cov.: 31 AF XY: 0.00279 AC XY: 2028 AN XY: 726942

African (AFR) AF: 0.114 AC: 3807 AN: 33410

American (AMR) AF: 0.00618 AC: 276 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39610

South Asian (SAS) AF: 0.000360 AC: 31 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5764

European-Non Finnish (NFE) AF: 0.000210 AC: 234 AN: 1111762

Other (OTH) AF: 0.00673 AC: 406 AN: 60344

GnomAD4 genome AF: 0.0301 AC: 4589 AN: 152294 Hom.: 245 Cov.: 32 AF XY: 0.0287 AC XY: 2139 AN XY: 74466

African (AFR) AF: 0.104 AC: 4314 AN: 41546

American (AMR) AF: 0.0128 AC: 196 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68024

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0115 Hom.: 174

Bravo AF: 0.0348

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.101 AC: 365

ESP6500EA AF: 0.000369 AC: 3

ExAC AF: 0.00985 AC: 1189

Asia WGS AF: 0.00953 AC: 33 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.000415

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)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	SYNE2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.0030
DANN	Benign	0.67
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.8
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.11
Sift	Benign	0.27	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.28		Loss of methylation at K1188 (P = 0.0537)
MVP		0.092
MPC		0.047
ClinPred		0.0028	T
GERP RS		-12
Varity_R		0.037
gMVP		0.070
Mutation Taster		=295/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs57259697; hg19: chr14-64467358;