NM_015374.3:c.166G>C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015374.3(SUN2):​c.166G>C​(p.Ala56Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000756 in 1,613,954 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: 𝑓 0.00038 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00079 (2 hom.)
• Consequence: SUN2 NM_015374.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0847235).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN2	NM_015374.3	MANE Select	c.166G>C	p.Ala56Pro	missense	Exon 3 of 18	NP_056189.1
	SUN2	NM_001394427.1		c.166G>C	p.Ala56Pro	missense	Exon 3 of 19	NP_001381356.1
	SUN2	NM_001199579.2		c.166G>C	p.Ala56Pro	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>C	p.Ala56Pro	missense	Exon 3 of 18	ENSP00000508608.1
	SUN2	ENST00000405018.5	TSL:1	c.166G>C	p.Ala56Pro	missense	Exon 3 of 18	ENSP00000385616.1
	SUN2	ENST00000405510.5	TSL:1	c.166G>C	p.Ala56Pro	missense	Exon 4 of 19	ENSP00000385740.1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000462 AC: 116 AN: 251208 AF XY: 0.000479

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000915

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000795 AC: 1162 AN: 1461762 Hom.: 2 Cov.: 32 AF XY: 0.000762 AC XY: 554 AN XY: 727176

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53322

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

European-Non Finnish (NFE) AF: 0.00102 AC: 1129 AN: 1111996

Other (OTH) AF: 0.000331 AC: 20 AN: 60394

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.000323 AC XY: 24 AN XY: 74348

African (AFR) AF: 0.000145 AC: 6 AN: 41434

American (AMR) AF: 0.000327 AC: 5 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000609 Hom.: 0

Bravo AF: 0.000446

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000552 AC: 67

EpiCase AF: 0.000872

EpiControl AF: 0.00142

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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	0.090
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.6
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.071	T
Polyphen		0.77	P
Vest4		0.70
MVP		0.55
MPC		0.88
ClinPred		0.023	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.50
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;