rs2072799

Positions:

• chr22-38752532-T-C

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.97A>G​(p.Thr33Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,613,768 control chromosomes in the GnomAD database, including 685 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (86 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (599 hom.)
• Consequence: SUN2 NM_015374.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.170

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013588965).
• BP6: Variant 22-38752532-T-C is Benign according to our data. Variant chr22-38752532-T-C is described in ClinVar as [Benign]. Clinvar id is 461693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUN2	NM_015374.3	c.97A>G	p.Thr33Ala	missense_variant	2/18	ENST00000689035.1	NP_056189.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUN2	ENST00000689035.1	c.97A>G	p.Thr33Ala	missense_variant	2/18		NM_015374.3	ENSP00000508608	P2

Frequencies

GnomAD3 genomes AF: 0.00791 AC: 1204 AN: 152212 Hom.: 85 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00960

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.0150 AC: 3748 AN: 249948 Hom.: 315 AF XY: 0.0140 AC XY: 1894 AN XY: 135240

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.178

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.00946

Gnomad NFE exome AF: 0.000738

Gnomad OTH exome AF: 0.00965

GnomAD4 exome AF: 0.00589 AC: 8607 AN: 1461438 Hom.: 599 Cov.: 32 AF XY: 0.00574 AC XY: 4176 AN XY: 727010

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.00260

Gnomad4 FIN exome AF: 0.00874

Gnomad4 NFE exome AF: 0.000486

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.00790 AC: 1204 AN: 152330 Hom.: 86 Cov.: 33 AF XY: 0.00885 AC XY: 659 AN XY: 74490

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.177

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00960

Gnomad4 NFE AF: 0.000808

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00646 Hom.: 116

Bravo AF: 0.00795

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0143 AC: 1737

Asia WGS AF: 0.0570 AC: 197 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Emery-Dreifuss muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.050	T;.;T;.;.;.;.;.;.;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.49	.;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0014	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;L;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.0	N;N;N;N;N;D;D;D;D;D
REVEL	Benign	0.14
Sift	Benign	0.14	T;T;T;T;T;D;T;T;D;T
Sift4G	Benign	0.067	T;T;T;T;.;.;.;T;.;.
Polyphen		0.14	B;.;B;.;.;.;.;.;.;.
Vest4		0.036
MPC		0.23
ClinPred		0.0029	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.027
gMVP		0.26

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: rs2072799; hg19: chr22-39148537; COSMIC: COSV53305493; COSMIC: COSV53305493;