14-63942134-G-C

Variant names:

• chr14-63942134-G-C
• rs33976862
• NM_182914.3:c.399G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_182914.3(SYNE2):​c.399G>C​(p.Leu133Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0794 in 1,578,694 control chromosomes in the GnomAD database, including 6,239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L133L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1276 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4963 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.888
• Publications: 8 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-63942134-G-C is Benign according to our data. Variant chr14-63942134-G-C is described in ClinVar as Benign. ClinVar VariationId is 130496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.888 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.208 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.399G>C	p.Leu133Leu	synonymous	Exon 6 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.399G>C	p.Leu133Leu	synonymous	Exon 6 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.399G>C	p.Leu133Leu	synonymous	Exon 6 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.399G>C	p.Leu133Leu	synonymous	Exon 6 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000341472.9	TSL:1	c.399G>C	p.Leu133Leu	synonymous	Exon 6 of 9	ENSP00000344528.5	Q8WXH0-8

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16844 AN: 151998 Hom.: 1271 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.0521

Gnomad SAS AF: 0.0387

Gnomad FIN AF: 0.0375

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0734

Gnomad OTH AF: 0.0891

GnomAD2 exomes AF: 0.0847 AC: 21015 AN: 248130 AF XY: 0.0776

Gnomad AFR exome AF: 0.222

Gnomad AMR exome AF: 0.165

Gnomad ASJ exome AF: 0.0515

Gnomad EAS exome AF: 0.0414

Gnomad FIN exome AF: 0.0432

Gnomad NFE exome AF: 0.0717

Gnomad OTH exome AF: 0.0738

GnomAD4 exome AF: 0.0761 AC: 108526 AN: 1426578 Hom.: 4963 Cov.: 27 AF XY: 0.0738 AC XY: 52550 AN XY: 711984

African (AFR) AF: 0.221 AC: 7176 AN: 32530

American (AMR) AF: 0.158 AC: 7054 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.0515 AC: 1336 AN: 25946

East Asian (EAS) AF: 0.0734 AC: 2899 AN: 39482

South Asian (SAS) AF: 0.0377 AC: 3226 AN: 85630

European-Finnish (FIN) AF: 0.0434 AC: 2256 AN: 51946

Middle Eastern (MID) AF: 0.0255 AC: 145 AN: 5688

European-Non Finnish (NFE) AF: 0.0741 AC: 80112 AN: 1081446

Other (OTH) AF: 0.0729 AC: 4322 AN: 59248

GnomAD4 genome AF: 0.111 AC: 16870 AN: 152116 Hom.: 1276 Cov.: 32 AF XY: 0.108 AC XY: 8009 AN XY: 74400

African (AFR) AF: 0.212 AC: 8769 AN: 41444

American (AMR) AF: 0.120 AC: 1837 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 184 AN: 3470

East Asian (EAS) AF: 0.0519 AC: 269 AN: 5186

South Asian (SAS) AF: 0.0383 AC: 185 AN: 4826

European-Finnish (FIN) AF: 0.0375 AC: 397 AN: 10598

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0734 AC: 4991 AN: 68004

Other (OTH) AF: 0.0882 AC: 186 AN: 2110

Alfa AF: 0.0801 Hom.: 198

Bravo AF: 0.124

Asia WGS AF: 0.0600 AC: 210 AN: 3478

EpiCase AF: 0.0685

EpiControl AF: 0.0644

ClinVar

ClinVar submissions as Germline

Significance: 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
BayesDel_noAF	Benign	-0.46
CADD	Benign	10
DANN	Benign	0.81
PhyloP100		0.89
Mutation Taster		=215/85	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: rs33976862; hg19: chr14-64408852; COSMIC: COSV58359815;