rs535438406

Positions:

• chr14-64003284-A-C
• chr14-64003284-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000555002.6(SYNE2):​c.4351A>C​(p.Ser1451Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1451G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SYNE2 ENST00000555002.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.789

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.4351A>C	p.Ser1451Arg	missense_variant	30/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.4351A>C	p.Ser1451Arg	missense_variant	30/116	1	NM_182914.3	ENSP00000450831	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461808 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	.;T;T;T
Eigen	Benign	0.065
Eigen_PC	Benign	0.088
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.85	D;D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;M;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.1	N;.;N;N
REVEL	Benign	0.050
Sift	Benign	0.11	T;.;T;T
Sift4G	Uncertain	0.039	D;D;D;D
Polyphen		0.92	P;.;P;.
Vest4		0.33
MutPred		0.29		Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);Gain of MoRF binding (P = 0.0221);
MVP		0.39
MPC		0.31
ClinPred		0.87	D
GERP RS		3.5
Varity_R		0.093
gMVP		0.11

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: rs535438406; hg19: chr14-64470002;