rs141051927

Variant names:

• chr22-38740321-C-T
• rs141051927
• NM_015374.3:c.1302G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_015374.3(SUN2):​c.1302G>A​(p.Ser434Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,602,598 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (10 hom.)
• Consequence: SUN2 NM_015374.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.59
• Publications: 1 publications found

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]

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]

GTPBP1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1

  Inheritance: AR Classification: MODERATE Submitted by: G2P

ENSG00000225450 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 22-38740321-C-T is Benign according to our data. Variant chr22-38740321-C-T is described in ClinVar as Benign. ClinVar VariationId is 530832.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.59 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015374.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN2	NM_015374.3	MANE Select	c.1302G>A	p.Ser434Ser	synonymous	Exon 12 of 18	NP_056189.1
	SUN2	NM_001394427.1		c.1395G>A	p.Ser465Ser	synonymous	Exon 13 of 19	NP_001381356.1
	SUN2	NM_001199579.2		c.1365G>A	p.Ser455Ser	synonymous	Exon 12 of 18	NP_001186508.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN2	ENST00000689035.1	MANE Select	c.1302G>A	p.Ser434Ser	synonymous	Exon 12 of 18	ENSP00000508608.1
	SUN2	ENST00000405018.5	TSL:1	c.1365G>A	p.Ser455Ser	synonymous	Exon 12 of 18	ENSP00000385616.1
	SUN2	ENST00000405510.5	TSL:1	c.1302G>A	p.Ser434Ser	synonymous	Exon 13 of 19	ENSP00000385740.1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 311 AN: 152176 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00198 AC: 445 AN: 224846 AF XY: 0.00187

Gnomad AFR exome AF: 0.000378

Gnomad AMR exome AF: 0.0000306

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00109

GnomAD4 exome AF: 0.00202 AC: 2935 AN: 1450422 Hom.: 10 Cov.: 31 AF XY: 0.00194 AC XY: 1397 AN XY: 720780

African (AFR) AF: 0.000301 AC: 10 AN: 33262

American (AMR) AF: 0.0000458 AC: 2 AN: 43632

Ashkenazi Jewish (ASJ) AF: 0.0000774 AC: 2 AN: 25856

East Asian (EAS) AF: 0.00 AC: 0 AN: 39198

South Asian (SAS) AF: 0.0000355 AC: 3 AN: 84416

European-Finnish (FIN) AF: 0.0123 AC: 631 AN: 51426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5230

European-Non Finnish (NFE) AF: 0.00200 AC: 2214 AN: 1107572

Other (OTH) AF: 0.00122 AC: 73 AN: 59830

GnomAD4 genome AF: 0.00204 AC: 311 AN: 152176 Hom.: 2 Cov.: 32 AF XY: 0.00248 AC XY: 184 AN XY: 74342

African (AFR) AF: 0.000338 AC: 14 AN: 41444

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0129 AC: 137 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00229 AC: 156 AN: 68026

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00122

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Emery-Dreifuss muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.046
DANN	Benign	0.82
PhyloP100		-4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs141051927; hg19: chr22-39136326;