rs143392390

Variant names:

• chr22-38750284-C-T
• rs143392390
• NM_015374.3:c.461G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_015374.3(SUN2):​c.461G>A​(p.Arg154Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R154W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: SUN2 NM_015374.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.04
• Publications: 3 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070873797).
• BP6: Variant 22-38750284-C-T is Benign according to our data. Variant chr22-38750284-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 530848.Status of the report is criteria_provided_single_submitter, 1 stars.

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.461G>A	p.Arg154Gln	missense	Exon 5 of 18	NP_056189.1	Q9UH99-1
	SUN2	NM_001394427.1		c.461G>A	p.Arg154Gln	missense	Exon 5 of 19	NP_001381356.1
	SUN2	NM_001199579.2		c.524G>A	p.Arg175Gln	missense	Exon 5 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.461G>A	p.Arg154Gln	missense	Exon 5 of 18	ENSP00000508608.1	Q9UH99-1
	SUN2	ENST00000405018.5	TSL:1	c.524G>A	p.Arg175Gln	missense	Exon 5 of 18	ENSP00000385616.1	Q9UH99-2
	SUN2	ENST00000405510.5	TSL:1	c.461G>A	p.Arg154Gln	missense	Exon 6 of 19	ENSP00000385740.1	Q9UH99-1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000243 AC: 61 AN: 250982 AF XY: 0.000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000970

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000148 AC: 217 AN: 1461550 Hom.: 0 Cov.: 32 AF XY: 0.000139 AC XY: 101 AN XY: 727084

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00390 AC: 102 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000863 AC: 96 AN: 1111920

Other (OTH) AF: 0.000298 AC: 18 AN: 60390

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74490

African (AFR) AF: 0.0000240 AC: 1 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000227 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Emery-Dreifuss muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.0
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.14
Sift	Benign	0.39	T
Sift4G	Benign	0.57	T
Polyphen		0.85	P
Vest4		0.18
MVP		0.54
MPC		0.28
ClinPred		0.061	T
GERP RS		5.1
Varity_R		0.068
gMVP		0.43
Mutation Taster		=90/10	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: rs143392390; hg19: chr22-39146289;