rs376340507

chr22-38740365-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015374.3(SUN2):c.1258G>A(p.Gly420Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000443 in 1,578,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: SUN2 NM_015374.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0890

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:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049504936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUN2	NM_015374.3	c.1258G>A	p.Gly420Ser	missense_variant	12/18	ENST00000689035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN2	ENST00000689035.1	c.1258G>A	p.Gly420Ser	missense_variant	12/18		NM_015374.3	P2
	ENST00000416406.1	n.165+1198C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000426 AC: 8 AN: 187810 Hom.: 0 AF XY: 0.0000294 AC XY: 3 AN XY: 101994

Gnomad AFR exome AF: 0.000379

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000792

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000254

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000329 AC: 47 AN: 1426450 Hom.: 0 Cov.: 31 AF XY: 0.0000326 AC XY: 23 AN XY: 706450

Gnomad4 AFR exome AF: 0.000213

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000788

Gnomad4 SAS exome AF: 0.0000734

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000238

Gnomad4 OTH exome AF: 0.0000848

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74338

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000773 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.000458 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000167 AC: 2

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Emery-Dreifuss muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 420 of the SUN2 protein (p.Gly420Ser). This variant is present in population databases (rs376340507, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SUN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 530824). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	9.8
Dann	Benign	0.88
DEOGEN2	Benign	0.019	T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.58	D
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.050	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.42	N;.;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.020	N;N;N
REVEL	Benign	0.043
Sift	Benign	0.46	T;T;T
Sift4G	Benign	0.77	T;T;T
Polyphen		0.018	B;.;B
Vest4		0.14
MVP		0.095
MPC		0.24
ClinPred		0.020	T
GERP RS		0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.21

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: rs376340507; hg19: chr22-39136370; COSMIC: COSV53302110; COSMIC: COSV53302110;