rs139238702

chr14-63949937-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_182914.3(SYNE2):c.521A>G(p.Lys174Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.62

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009234786).
• BP6: Variant 14-63949937-A-G is Benign according to our data. Variant chr14-63949937-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212345.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00046 (70/152264) while in subpopulation AFR AF= 0.00159 (66/41550). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 71 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.521A>G	p.Lys174Arg	missense_variant	7/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.521A>G	p.Lys174Arg	missense_variant	7/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000124 AC: 31 AN: 249564 Hom.: 0 AF XY: 0.0000960 AC XY: 13 AN XY: 135396

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37 AN XY: 727242

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74452

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.000131

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: 0.000947

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.000567

ESP6500AA AF: 0.000748 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 04, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 02, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	16
Dann	Benign	0.69
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.66
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.73	T;T;T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.0092	T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.4	L;.;L;L;.
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N;.;N;N;N
REVEL	Benign	0.055
Sift	Benign	0.067	T;.;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.058	B;.;B;B;.
Vest4		0.079
MVP		0.62
MPC		0.043
ClinPred		0.0047	T
GERP RS		0.59
Varity_R		0.047
gMVP		0.25

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: rs139238702; hg19: chr14-64416655;