rs138708

Positions:

• chr22-38742327-G-A
• chr22-38742327-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015374.3(SUN2):​c.1042C>T​(p.Arg348Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0216 in 1,605,716 control chromosomes in the GnomAD database, including 733 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R348H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (49 hom., cov: 32)
  • Exomes 𝑓: 0.022 (684 hom.)
• Consequence: SUN2 NM_015374.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.99

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023243427).
• BP6: Variant 22-38742327-G-A is Benign according to our data. Variant chr22-38742327-G-A is described in ClinVar as [Benign]. Clinvar id is 461670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38742327-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUN2	NM_015374.3	c.1042C>T	p.Arg348Cys	missense_variant	9/18	ENST00000689035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN2	ENST00000689035.1	c.1042C>T	p.Arg348Cys	missense_variant	9/18		NM_015374.3	P2
	ENST00000416406.1	n.165+3160G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2602 AN: 152114 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.00661

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.0983

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0200

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.0216 AC: 5397 AN: 249838 Hom.: 132 AF XY: 0.0214 AC XY: 2890 AN XY: 135118

Gnomad AFR exome AF: 0.00672

Gnomad AMR exome AF: 0.00816

Gnomad ASJ exome AF: 0.0250

Gnomad EAS exome AF: 0.0932

Gnomad SAS exome AF: 0.0139

Gnomad FIN exome AF: 0.00686

Gnomad NFE exome AF: 0.0210

Gnomad OTH exome AF: 0.0187

GnomAD4 exome AF: 0.0220 AC: 32007 AN: 1453484 Hom.: 684 Cov.: 31 AF XY: 0.0217 AC XY: 15624 AN XY: 721264

Gnomad4 AFR exome AF: 0.00530

Gnomad4 AMR exome AF: 0.00964

Gnomad4 ASJ exome AF: 0.0241

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.00693

Gnomad4 NFE exome AF: 0.0205

Gnomad4 OTH exome AF: 0.0217

GnomAD4 genome AF: 0.0171 AC: 2603 AN: 152232 Hom.: 49 Cov.: 32 AF XY: 0.0166 AC XY: 1235 AN XY: 74430

Gnomad4 AFR AF: 0.00659

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.0231

Gnomad4 EAS AF: 0.0983

Gnomad4 SAS AF: 0.0201

Gnomad4 FIN AF: 0.00480

Gnomad4 NFE AF: 0.0200

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0224 Hom.: 101

Bravo AF: 0.0178

TwinsUK AF: 0.0202 AC: 75

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.0200 AC: 172

ExAC AF: 0.0221 AC: 2680

Asia WGS AF: 0.0500 AC: 173 AN: 3478

EpiCase AF: 0.0194

EpiControl AF: 0.0228

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Emery-Dreifuss muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;D;D
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.32
MPC		0.92
ClinPred		0.0089	T
GERP RS		5.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.22
gMVP		0.33

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: rs138708; hg19: chr22-39138332; COSMIC: COSV53306865; COSMIC: COSV53306865;