rs758076166
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_015374.3(SUN2):c.1633G>A(p.Gly545Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
SUN2
NM_015374.3 missense
NM_015374.3 missense
Scores
7
6
5
Clinical Significance
Conservation
PhyloP100: 4.89
Genes affected
SUN2 (HGNC:14210): (Sad1 and UNC84 domain containing 2) SUN1 (MIM 607723) and SUN2 are inner nuclear membrane (INM) proteins that play a major role in nuclear-cytoplasmic connection by formation of a 'bridge' across the nuclear envelope, known as the LINC complex, via interaction with the conserved luminal KASH domain of nesprins (e.g., SYNE1; MIM 608441) located in the outer nuclear membrane (ONM). The LINC complex provides a direct connection between the nuclear lamina and the cytoskeleton, which contributes to nuclear positioning and cellular rigidity (summary by Haque et al., 2010 [PubMed 19933576]).[supplied by OMIM, Nov 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SUN2 | NM_015374.3 | c.1633G>A | p.Gly545Arg | missense_variant | 14/18 | ENST00000689035.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SUN2 | ENST00000689035.1 | c.1633G>A | p.Gly545Arg | missense_variant | 14/18 | NM_015374.3 | P2 | ||
ENST00000416406.1 | n.165+205C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250162Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135492
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135492
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460798Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 726692
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
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Cov.:
33
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Emery-Dreifuss muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2018 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with SUN2-related disease. This variant is present in population databases (rs758076166, ExAC 0.002%). This sequence change replaces glycine with arginine at codon 545 of the SUN2 protein (p.Gly545Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;.;M;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Benign
Sift
Pathogenic
D;D;D;D
Sift4G
Pathogenic
D;D;D;T
Polyphen
D;.;D;.
Vest4
MutPred
Gain of helix (P = 0.0022);.;Gain of helix (P = 0.0022);.;
MVP
MPC
0.95
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at