rs190518140

chr14-64070723-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_182914.3(SYNE2):c.10510A>G(p.Thr3504Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000496 in 1,614,178 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.72

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00614202).
• BP6: Variant 14-64070723-A-G is Benign according to our data. Variant chr14-64070723-A-G is described in ClinVar as [Benign]. Clinvar id is 470911.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-64070723-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00264 (402/152340) while in subpopulation AFR AF= 0.00895 (372/41576). AF 95% confidence interval is 0.0082. There are 1 homozygotes in gnomad4. There are 188 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 400 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.10510A>G	p.Thr3504Ala	missense_variant	52/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.10510A>G	p.Thr3504Ala	missense_variant	52/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.00263 AC: 400 AN: 152222 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

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: 0.000955

GnomAD3 exomes AF: 0.000653 AC: 163 AN: 249512 Hom.: 1 AF XY: 0.000569 AC XY: 77 AN XY: 135372

Gnomad AFR exome AF: 0.00930

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000272 AC: 398 AN: 1461838 Hom.: 1 Cov.: 33 AF XY: 0.000226 AC XY: 164 AN XY: 727224

Gnomad4 AFR exome AF: 0.00956

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.00264 AC: 402 AN: 152340 Hom.: 1 Cov.: 33 AF XY: 0.00252 AC XY: 188 AN XY: 74498

Gnomad4 AFR AF: 0.00895

Gnomad4 AMR AF: 0.00183

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: 0.000945

Alfa AF: 0.000596 Hom.: 0

Bravo AF: 0.00323

ESP6500AA AF: 0.00947 AC: 35

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000911 AC: 110

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	15
Dann	Benign	0.95
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.60	T;T;T;T;T
MetaRNN	Benign	0.0061	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.;M;.;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.5	N;.;N;N;N
REVEL	Benign	0.070
Sift	Benign	0.048	D;.;T;D;T
Sift4G	Benign	0.10	T;T;T;T;T
Polyphen		0.57	P;.;B;.;.
Vest4		0.35
MVP		0.30
MPC		0.19
ClinPred		0.016	T
GERP RS		4.3
Varity_R		0.053
gMVP		0.10

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: rs190518140; hg19: chr14-64537441;