rs2072797

Positions:

• chr22-38738202-C-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.2011G>A​(p.Gly671Ser) variant causes a missense change. The variant allele was found at a frequency of 0.11 in 1,613,644 control chromosomes in the GnomAD database, including 10,681 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. G671G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.090 (831 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9850 hom.)
• Consequence: SUN2 NM_015374.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.80

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:):

GTPBP1 (HGNC:4669): (GTP binding protein 1) This gene is upregulated by interferon-gamma and encodes a protein that is a member of the AGP11/GTPBP1 family of GTP-binding proteins. A structurally similar protein has been found in mouse, where disruption of the gene for that protein had no observable phenotype. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016545057).
• BP6: Variant 22-38738202-C-T is Benign according to our data. Variant chr22-38738202-C-T is described in ClinVar as [Benign]. Clinvar id is 1168063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUN2	NM_015374.3	c.2011G>A	p.Gly671Ser	missense_variant	17/18	ENST00000689035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN2	ENST00000689035.1	c.2011G>A	p.Gly671Ser	missense_variant	17/18		NM_015374.3	P2
	ENST00000418803.1	n.86-225C>T		intron_variant, non_coding_transcript_variant		5
	ENST00000420118.1	n.318-420C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0900 AC: 13689 AN: 152030 Hom.: 834 Cov.: 32

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.0678

Gnomad ASJ AF: 0.0919

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.0906

GnomAD3 exomes AF: 0.109 AC: 27287 AN: 251384 Hom.: 1786 AF XY: 0.112 AC XY: 15265 AN XY: 135888

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.0458

Gnomad ASJ exome AF: 0.0866

Gnomad EAS exome AF: 0.181

Gnomad SAS exome AF: 0.125

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.112 AC: 164218 AN: 1461496 Hom.: 9850 Cov.: 32 AF XY: 0.113 AC XY: 81885 AN XY: 727066

Gnomad4 AFR exome AF: 0.0171

Gnomad4 AMR exome AF: 0.0495

Gnomad4 ASJ exome AF: 0.0925

Gnomad4 EAS exome AF: 0.160

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.160

Gnomad4 NFE exome AF: 0.114

Gnomad4 OTH exome AF: 0.107

GnomAD4 genome AF: 0.0899 AC: 13680 AN: 152148 Hom.: 831 Cov.: 32 AF XY: 0.0925 AC XY: 6881 AN XY: 74378

Gnomad4 AFR AF: 0.0207

Gnomad4 AMR AF: 0.0677

Gnomad4 ASJ AF: 0.0919

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.161

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.0897

Alfa AF: 0.108 Hom.: 1948

Bravo AF: 0.0823

TwinsUK AF: 0.115 AC: 427

ALSPAC AF: 0.124 AC: 477

ESP6500AA AF: 0.0213 AC: 94

ESP6500EA AF: 0.114 AC: 977

ExAC AF: 0.109 AC: 13251

Asia WGS AF: 0.137 AC: 479 AN: 3478

EpiCase AF: 0.113

EpiControl AF: 0.115

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 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

This variant is associated with the following publications: (PMID: 17827388) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	L;.;L;.
MutationTaster	Benign	3.7e-7	P;P;P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.5	D;D;D;D
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D
Polyphen		0.35	B;.;B;.
Vest4		0.28
MPC		0.69
ClinPred		0.046	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs2072797; hg19: chr22-39134207; COSMIC: COSV53283367; COSMIC: COSV53283367;