rs374980509

chr14-64002923-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_182914.3(SYNE2):c.3990G>A(p.Ala1330=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,614,140 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00061 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.36

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-64002923-G-A is Benign according to our data. Variant chr14-64002923-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 538358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000611 (93/152270) while in subpopulation AFR AF= 0.00183 (76/41554). AF 95% confidence interval is 0.0015. There are 1 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 94 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.3990G>A	p.Ala1330=	synonymous_variant	30/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.3990G>A	p.Ala1330=	synonymous_variant	30/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152152 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000169 AC: 42 AN: 249154 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135160

Gnomad AFR exome AF: 0.00233

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.0000468 AC XY: 34 AN XY: 727230

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152270 Hom.: 1 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74442

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.000797

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

SYNE2: BP4, BP7 -

SYNE2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	5.1
Dann	Benign	0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs374980509; hg19: chr14-64469641; COSMIC: COSV59938236; COSMIC: COSV59938236;