rs147351772

chr22-38740269-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_015374.3(SUN2):c.1354G>A(p.Asp452Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,576,052 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. D452D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (10 hom.)
• Consequence: SUN2 NM_015374.3 missense, splice_region
• Scores: Splicing: ADA: 0.0005564
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.58

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008936048).
• BP6: Variant 22-38740269-C-T is Benign according to our data. Variant chr22-38740269-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 461674.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUN2	NM_015374.3	c.1354G>A	p.Asp452Asn	missense_variant, splice_region_variant	12/18	ENST00000689035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN2	ENST00000689035.1	c.1354G>A	p.Asp452Asn	missense_variant, splice_region_variant	12/18		NM_015374.3	P2
	ENST00000416406.1	n.165+1102C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 306 AN: 152184 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00160 AC: 343 AN: 214030 Hom.: 2 AF XY: 0.00142 AC XY: 166 AN XY: 117074

Gnomad AFR exome AF: 0.00298

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000772

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00119

Gnomad OTH exome AF: 0.00389

GnomAD4 exome AF: 0.00119 AC: 1698 AN: 1423750 Hom.: 10 Cov.: 31 AF XY: 0.00121 AC XY: 851 AN XY: 704034

Gnomad4 AFR exome AF: 0.00326

Gnomad4 AMR exome AF: 0.00205

Gnomad4 ASJ exome AF: 0.0150

Gnomad4 EAS exome AF: 0.0000516

Gnomad4 SAS exome AF: 0.0000736

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000849

Gnomad4 OTH exome AF: 0.00291

GnomAD4 genome AF: 0.00200 AC: 305 AN: 152302 Hom.: 2 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74466

Gnomad4 AFR AF: 0.00339

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00211 Hom.: 3

Bravo AF: 0.00228

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00228 AC: 10

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00123 AC: 149

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Emery-Dreifuss muscular dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	22
Dann	Benign	0.96
DEOGEN2	Benign	0.12	T;.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0089	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.;M
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.072
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.99	D;.;D
Vest4		0.46
MVP		0.49
MPC		0.70
ClinPred		0.027	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.079
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00056
dbscSNV1_RF	Benign	0.010
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: rs147351772; hg19: chr22-39136274; COSMIC: COSV53302211; COSMIC: COSV53302211;