rs2092804001

Variant names:

• chr22-38736281-C-T
• rs2092804001
• NM_015374.3:c.2140G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015374.3(SUN2):​c.2140G>A​(p.Glu714Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SUN2 NM_015374.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.38
• Publications: 0 publications found

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]

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1

  Inheritance: AR Classification: MODERATE Submitted by: G2P

ENSG00000230149 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27798402).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015374.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN2	NM_015374.3	MANE Select	c.2140G>A	p.Glu714Lys	missense	Exon 18 of 18	NP_056189.1	Q9UH99-1
	SUN2	NM_001394427.1		c.2233G>A	p.Glu745Lys	missense	Exon 19 of 19	NP_001381356.1
	SUN2	NM_001199579.2		c.2203G>A	p.Glu735Lys	missense	Exon 18 of 18	NP_001186508.1	Q9UH99-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN2	ENST00000689035.1	MANE Select	c.2140G>A	p.Glu714Lys	missense	Exon 18 of 18	ENSP00000508608.1	Q9UH99-1
	SUN2	ENST00000405018.5	TSL:1	c.2203G>A	p.Glu735Lys	missense	Exon 18 of 18	ENSP00000385616.1	Q9UH99-2
	SUN2	ENST00000405510.5	TSL:1	c.2140G>A	p.Glu714Lys	missense	Exon 19 of 19	ENSP00000385740.1	Q9UH99-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461032 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726814

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111572

Other (OTH) AF: 0.0000166 AC: 1 AN: 60330

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Emery-Dreifuss muscular dystrophy (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.098
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.074
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.86	P
Vest4		0.10
MutPred		0.50		Gain of MoRF binding (P = 5e-04)
MVP		0.64
MPC		0.85
ClinPred		0.90	D
GERP RS		5.3
Varity_R		0.64
gMVP		0.56
Mutation Taster		=52/48	polymorphism

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

Other links and lift over

dbSNP: rs2092804001; hg19: chr22-39132286; COSMIC: COSV53286180; COSMIC: COSV53286180;