22-38751330-C-T

Variant names:

• chr22-38751330-C-T
• rs137966643
• NM_015374.3:c.166G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001394427.1(SUN2):​c.166G>A​(p.Ala56Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. A56V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SUN2 NM_001394427.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• Publications: 5 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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06531882).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394427.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN2	NM_015374.3	MANE Select	c.166G>A	p.Ala56Thr	missense	Exon 3 of 18	NP_056189.1
	SUN2	NM_001394427.1		c.166G>A	p.Ala56Thr	missense	Exon 3 of 19	NP_001381356.1
	SUN2	NM_001199579.2		c.166G>A	p.Ala56Thr	missense	Exon 3 of 18	NP_001186508.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN2	ENST00000689035.1	MANE Select	c.166G>A	p.Ala56Thr	missense	Exon 3 of 18	ENSP00000508608.1
	SUN2	ENST00000405018.5	TSL:1	c.166G>A	p.Ala56Thr	missense	Exon 3 of 18	ENSP00000385616.1
	SUN2	ENST00000405510.5	TSL:1	c.166G>A	p.Ala56Thr	missense	Exon 4 of 19	ENSP00000385740.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.12
Sift	Benign	0.072	T
Sift4G	Benign	0.41	T
Polyphen		0.0060	B
Vest4		0.21
MutPred		0.12		Gain of phosphorylation at A56 (P = 0.0162)
MVP		0.34
MPC		0.56
ClinPred		0.31	T
GERP RS		4.3
Varity_R		0.037
gMVP		0.38
Mutation Taster		=54/46	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: rs137966643; hg19: chr22-39147335;