rs537241816

Variant names:

• chr22-38738918-G-A
• rs537241816
• NM_015374.3:c.1734C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-38738918-G-A
• chr22-38738918-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_015374.3(SUN2):​c.1734C>T​(p.Gly578Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000362 in 1,612,458 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. G578G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (11 hom.)
• Consequence: SUN2 NM_015374.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.667
• Publications: 0 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]

ENSG00000230149 (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]

GTPBP1 Gene-Disease associations (from GenCC):

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

  Inheritance: AR Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 22-38738918-G-A is Benign according to our data. Variant chr22-38738918-G-A is described in ClinVar as Benign. ClinVar VariationId is 530852.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 11 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.1734C>T	p.Gly578Gly	synonymous	Exon 15 of 18	NP_056189.1
	SUN2	NM_001394427.1		c.1827C>T	p.Gly609Gly	synonymous	Exon 16 of 19	NP_001381356.1
	SUN2	NM_001199579.2		c.1797C>T	p.Gly599Gly	synonymous	Exon 15 of 18	NP_001186508.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN2	ENST00000689035.1	MANE Select	c.1734C>T	p.Gly578Gly	synonymous	Exon 15 of 18	ENSP00000508608.1
	SUN2	ENST00000405018.5	TSL:1	c.1797C>T	p.Gly599Gly	synonymous	Exon 15 of 18	ENSP00000385616.1
	SUN2	ENST00000405510.5	TSL:1	c.1734C>T	p.Gly578Gly	synonymous	Exon 16 of 19	ENSP00000385740.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000703 AC: 175 AN: 249036 AF XY: 0.000972

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000375 AC: 548 AN: 1460204 Hom.: 11 Cov.: 33 AF XY: 0.000549 AC XY: 399 AN XY: 726150

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.0000449 AC: 2 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00596 AC: 513 AN: 86098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111020

Other (OTH) AF: 0.000464 AC: 28 AN: 60308

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74448

African (AFR) AF: 0.00 AC: 0 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00746 AC: 36 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

Asia WGS AF: 0.00289 AC: 10 AN: 3478

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	-0.49
CADD	Benign	17
DANN	Benign	0.89
PhyloP100		-0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.46		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs537241816; hg19: chr22-39134923;