chr22-38741508-C-T

Variant names:

• chr22-38741508-C-T
• rs139004902
• NM_015374.3:c.1132G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_015374.3(SUN2):​c.1132G>A​(p.Val378Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00848 in 1,613,910 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (60 hom.)
• Consequence: SUN2 NM_015374.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.14
• Publications: 13 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047117174).
• BP6: Variant 22-38741508-C-T is Benign according to our data. Variant chr22-38741508-C-T is described in ClinVar as Benign. ClinVar VariationId is 461671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 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.1132G>A	p.Val378Ile	missense	Exon 10 of 18	NP_056189.1
	SUN2	NM_001394427.1		c.1225G>A	p.Val409Ile	missense	Exon 11 of 19	NP_001381356.1
	SUN2	NM_001199579.2		c.1195G>A	p.Val399Ile	missense	Exon 10 of 18	NP_001186508.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN2	ENST00000689035.1	MANE Select	c.1132G>A	p.Val378Ile	missense	Exon 10 of 18	ENSP00000508608.1
	SUN2	ENST00000405018.5	TSL:1	c.1195G>A	p.Val399Ile	missense	Exon 10 of 18	ENSP00000385616.1
	SUN2	ENST00000405510.5	TSL:1	c.1132G>A	p.Val378Ile	missense	Exon 11 of 19	ENSP00000385740.1

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 1068 AN: 152170 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00742 AC: 1862 AN: 251052 AF XY: 0.00751

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00596

Gnomad ASJ exome AF: 0.00983

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00930

GnomAD4 exome AF: 0.00863 AC: 12617 AN: 1461622 Hom.: 60 Cov.: 32 AF XY: 0.00858 AC XY: 6238 AN XY: 727118

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.00606 AC: 271 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00972 AC: 254 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00437 AC: 377 AN: 86254

European-Finnish (FIN) AF: 0.0107 AC: 567 AN: 53220

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.00956 AC: 10635 AN: 1111954

Other (OTH) AF: 0.00753 AC: 455 AN: 60390

GnomAD4 genome AF: 0.00701 AC: 1068 AN: 152288 Hom.: 3 Cov.: 32 AF XY: 0.00672 AC XY: 500 AN XY: 74460

African (AFR) AF: 0.00168 AC: 70 AN: 41548

American (AMR) AF: 0.00483 AC: 74 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00952 AC: 33 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4828

European-Finnish (FIN) AF: 0.0102 AC: 108 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0107 AC: 731 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00866 Hom.: 23

Bravo AF: 0.00611

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.0103 AC: 89

ExAC AF: 0.00801 AC: 972

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.0102

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Emery-Dreifuss muscular dystrophy Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.1
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.026
Sift	Benign	0.49	T
Sift4G	Benign	0.48	T
Polyphen		0.34	B
Vest4		0.097
MVP		0.29
MPC		0.19
ClinPred		0.0041	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.16
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: rs139004902; hg19: chr22-39137513; COSMIC: COSV99325976; COSMIC: COSV99325976;