22-38736380-C-T

Position:

chr22-38736380-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015374.3(SUN2):c.2041G>A(p.Ala681Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A681A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SUN2
NM_015374.3 missense, splice_region

Scores

Splicing: ADA: 0.0005395

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0500

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]

SUN2 links:

(HGNC:):

links:

GTPBP1 (HGNC:4669): (GTP binding protein 1) This gene is upregulated by interferon-gamma and encodes a protein that is a member of the AGP11/GTPBP1 family of GTP-binding proteins. A structurally similar protein has been found in mouse, where disruption of the gene for that protein had no observable phenotype. [provided by RefSeq, Jul 2008]

GTPBP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.01025635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUN2	NM_015374.3 linkuse as main transcript	c.2041G>A	p.Ala681Thr	missense_variant, splice_region_variant	18/18	ENST00000689035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN2	ENST00000689035.1 linkuse as main transcript	c.2041G>A	p.Ala681Thr	missense_variant, splice_region_variant	18/18		NM_015374.3	P2	Q9UH99-1
	ENST00000418803.1 linkuse as main transcript	n.85+1566C>T		intron_variant, non_coding_transcript_variant		5
	ENST00000420118.1 linkuse as main transcript	n.317+1339C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00000405

AC:

AN:

247182

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133768

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000294

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:

6.85e-7

AC:

AN:

1459158

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725936

show subpopulations

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

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

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

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

Jun 27, 2022

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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 838691). This variant has not been reported in the literature in individuals affected with SUN2-related conditions. This variant is present in population databases (rs559096453, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 681 of the SUN2 protein (p.Ala681Thr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.031

T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.39

M_CAP

Benign

0.016

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

L;.;L

MutationTaster

Benign

0.72

D;D;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.19

N;N;N

REVEL

Benign

0.031

Sift

Benign

0.59

T;T;T

Sift4G

Benign

0.37

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.081

MutPred

0.34

Gain of sheet (P = 0.1451);.;Gain of sheet (P = 0.1451);

MVP

0.16

MPC

0.23

ClinPred

0.020

GERP RS

-0.85

Varity_R

0.16

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00054

dbscSNV1_RF

Benign

0.064

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over