chr22-38736278-G-A

Position:

• chr22-38736278-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015374.3(SUN2):​c.2143C>T​(p.Pro715Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,422 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P715P) has been classified as Likely benign.

• 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, single submitter U:1
• Conservation: PhyloP100: 5.63

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]

(HGNC:):

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]

ACMG classification

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.2143C>T	p.Pro715Ser	missense_variant	18/18	ENST00000689035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN2	ENST00000689035.1	c.2143C>T	p.Pro715Ser	missense_variant	18/18		NM_015374.3	P2
	ENST00000418803.1	n.85+1464G>A		intron_variant, non_coding_transcript_variant		5
	ENST00000420118.1	n.317+1237G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460422 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726522

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2024

The c.2143C>T (p.P715S) alteration is located in exon 18 (coding exon 17) of the SUN2 gene. This alteration results from a C to T substitution at nucleotide position 2143, causing the proline (P) at amino acid position 715 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T;.;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.1	M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-7.0	D;D;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.47
MutPred		0.57		Gain of glycosylation at P715 (P = 0.0838);.;Gain of glycosylation at P715 (P = 0.0838);
MVP		0.63
MPC		0.87
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs1045770195; hg19: chr22-39132283;