22-38740269-C-A

Variant names:

• chr22-38740269-C-A
• rs147351772
• NM_015374.3:c.1354G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015374.3(SUN2):​c.1354G>T​(p.Asp452Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,423,754 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. D452N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SUN2 NM_015374.3 missense, splice_region
• Scores: Splicing: ADA: 0.02663
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58
• 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

ENSG00000225450 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1354G>T	p.Asp452Tyr	missense splice_region	Exon 12 of 18	NP_056189.1	Q9UH99-1
	SUN2	NM_001394427.1		c.1447G>T	p.Asp483Tyr	missense splice_region	Exon 13 of 19	NP_001381356.1
	SUN2	NM_001199579.2		c.1417G>T	p.Asp473Tyr	missense splice_region	Exon 12 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.1354G>T	p.Asp452Tyr	missense splice_region	Exon 12 of 18	ENSP00000508608.1	Q9UH99-1
	SUN2	ENST00000405018.5	TSL:1	c.1417G>T	p.Asp473Tyr	missense splice_region	Exon 12 of 18	ENSP00000385616.1	Q9UH99-2
	SUN2	ENST00000405510.5	TSL:1	c.1354G>T	p.Asp452Tyr	missense splice_region	Exon 13 of 19	ENSP00000385740.1	Q9UH99-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1423754 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 704036

African (AFR) AF: 0.00 AC: 0 AN: 32562

American (AMR) AF: 0.00 AC: 0 AN: 40930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24482

East Asian (EAS) AF: 0.00 AC: 0 AN: 38778

South Asian (SAS) AF: 0.00 AC: 0 AN: 81542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4208

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1091830

Other (OTH) AF: 0.00 AC: 0 AN: 58516

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	0.090
Eigen_PC	Benign	-0.0020
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.6
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.12
Sift	Benign	0.030	D
Sift4G	Uncertain	0.040	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.38		Loss of disorder (P = 0.0334)
MVP		0.41
MPC		0.95
ClinPred		0.90	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.61
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.027
dbscSNV1_RF	Benign	0.23
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: rs147351772; hg19: chr22-39136274;