22-38751330-C-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015374.3(SUN2):​c.166G>C​(p.Ala56Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000756 in 1,613,954 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A56V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00079 ( 2 hom. )

Consequence

SUN2
NM_015374.3 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.58

Publications

5 publications found
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0847235).
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SUN2NM_015374.3 linkc.166G>C p.Ala56Pro missense_variant Exon 3 of 18 ENST00000689035.1 NP_056189.1 Q9UH99-1A0A024R1P7B4E2A6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SUN2ENST00000689035.1 linkc.166G>C p.Ala56Pro missense_variant Exon 3 of 18 NM_015374.3 ENSP00000508608.1 Q9UH99-1

Frequencies

GnomAD3 genomes
AF:
0.000381
AC:
58
AN:
152192
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
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:
0.000691
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000462
AC:
116
AN:
251208
AF XY:
0.000479
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000915
Gnomad OTH exome
AF:
0.000653
GnomAD4 exome
AF:
0.000795
AC:
1162
AN:
1461762
Hom.:
2
Cov.:
32
AF XY:
0.000762
AC XY:
554
AN XY:
727176
show subpopulations
African (AFR)
AF:
0.000179
AC:
6
AN:
33480
American (AMR)
AF:
0.000134
AC:
6
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26128
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.0000188
AC:
1
AN:
53322
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00102
AC:
1129
AN:
1111996
Other (OTH)
AF:
0.000331
AC:
20
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.485
Heterozygous variant carriers
0
66
132
198
264
330
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
44
88
132
176
220
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000381
AC:
58
AN:
152192
Hom.:
0
Cov.:
33
AF XY:
0.000323
AC XY:
24
AN XY:
74348
show subpopulations
African (AFR)
AF:
0.000145
AC:
6
AN:
41434
American (AMR)
AF:
0.000327
AC:
5
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4838
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000691
AC:
47
AN:
68030
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.512
Heterozygous variant carriers
0
4
8
13
17
21
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000609
Hom.:
0
Bravo
AF:
0.000446
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.00182
AC:
7
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000698
AC:
6
ExAC
AF:
0.000552
AC:
67
EpiCase
AF:
0.000872
EpiControl
AF:
0.00142

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Emery-Dreifuss muscular dystrophy Uncertain:1
Jan 28, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 56 of the SUN2 protein (p.Ala56Pro). This variant is present in population databases (rs137966643, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SUN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 530819). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SUN2 function (PMID: 25210889). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.23
T;.;T;.;.;.;.;.;.;.
Eigen
Benign
-0.17
Eigen_PC
Benign
-0.20
FATHMM_MKL
Benign
0.31
N
LIST_S2
Benign
0.82
.;T;T;T;T;T;T;T;T;T
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.085
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
M;M;M;.;.;.;.;.;.;.
PhyloP100
1.6
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-2.1
N;N;N;N;D;D;D;D;D;D
REVEL
Pathogenic
0.66
Sift
Uncertain
0.0070
D;D;D;D;D;D;D;D;D;D
Sift4G
Benign
0.071
T;D;T;D;.;.;.;D;.;.
Polyphen
0.77
P;.;P;.;.;.;.;.;.;.
Vest4
0.70
MVP
0.55
MPC
0.88
ClinPred
0.023
T
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.26
gMVP
0.50
Mutation Taster
=0/100
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs137966643; hg19: chr22-39147335; API