rs374766665

chr14-64055984-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_182914.3(SYNE2):c.9785A>G(p.Lys3262Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 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 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.567

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 -9 ACMG points.

• BP6: Variant 14-64055984-A-G is Benign according to our data. Variant chr14-64055984-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436912.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000184 (28/152198) while in subpopulation AFR AF= 0.000675 (28/41456). AF 95% confidence interval is 0.000479. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.9785A>G	p.Lys3262Arg	missense_variant	49/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.9785A>G	p.Lys3262Arg	missense_variant	49/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD3 exomes AF: 0.0000602 AC: 15 AN: 249346 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135304

Gnomad AFR exome AF: 0.000969

Gnomad AMR exome AF: 0.00

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: 0.0000274 AC: 40 AN: 1461758 Hom.: 0 Cov.: 49 AF XY: 0.0000220 AC XY: 16 AN XY: 727192

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74356

Gnomad4 AFR AF: 0.000675

Gnomad4 AMR AF: 0.00

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: 0.00

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.000264

ESP6500AA AF: 0.00129 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000745 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 10, 2021	The c.9785A>G (p.K3262R) alteration is located in exon 49 (coding exon 48) of the SYNE2 gene. This alteration results from a A to G substitution at nucleotide position 9785, causing the lysine (K) at amino acid position 3262 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 16, 2016	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	14
Dann	Benign	0.88
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.66	T;T;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.014	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.32	N;.;N;N
REVEL	Benign	0.073
Sift	Benign	0.38	T;.;T;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.068	B;.;B;.
Vest4		0.057
MVP		0.21
MPC		0.042
ClinPred		0.022	T
GERP RS		4.5
Varity_R		0.027
gMVP		0.066

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs374766665; hg19: chr14-64522702;