22-38740267-G-A

Variant names:

• chr22-38740267-G-A
• rs138079219
• NM_015374.3:c.1356C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015374.3(SUN2):​c.1356C>T​(p.Asp452Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,573,900 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (27 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (22 hom.)
• Consequence: SUN2 NM_015374.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001975
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.66
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 22-38740267-G-A is Benign according to our data. Variant chr22-38740267-G-A is described in ClinVar as Benign. ClinVar VariationId is 461675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.66 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0095 (1447/152286) while in subpopulation AFR AF = 0.0339 (1407/41562). AF 95% confidence interval is 0.0324. There are 27 homozygotes in GnomAd4. There are 688 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 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.1356C>T	p.Asp452Asp	splice_region synonymous	Exon 12 of 18	NP_056189.1
	SUN2	NM_001394427.1		c.1449C>T	p.Asp483Asp	splice_region synonymous	Exon 13 of 19	NP_001381356.1
	SUN2	NM_001199579.2		c.1419C>T	p.Asp473Asp	splice_region 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.1356C>T	p.Asp452Asp	splice_region synonymous	Exon 12 of 18	ENSP00000508608.1
	SUN2	ENST00000405018.5	TSL:1	c.1419C>T	p.Asp473Asp	splice_region synonymous	Exon 12 of 18	ENSP00000385616.1
	SUN2	ENST00000405510.5	TSL:1	c.1356C>T	p.Asp452Asp	splice_region synonymous	Exon 13 of 19	ENSP00000385740.1

Frequencies

GnomAD3 genomes AF: 0.00948 AC: 1442 AN: 152168 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00246 AC: 522 AN: 211870 AF XY: 0.00186

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.000984

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000213

Gnomad OTH exome AF: 0.00176

GnomAD4 exome AF: 0.000959 AC: 1363 AN: 1421614 Hom.: 22 Cov.: 31 AF XY: 0.000861 AC XY: 605 AN XY: 702760

African (AFR) AF: 0.0359 AC: 1169 AN: 32528

American (AMR) AF: 0.00101 AC: 41 AN: 40622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24350

East Asian (EAS) AF: 0.00 AC: 0 AN: 38738

South Asian (SAS) AF: 0.0000862 AC: 7 AN: 81196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50808

Middle Eastern (MID) AF: 0.000719 AC: 3 AN: 4172

European-Non Finnish (NFE) AF: 0.0000220 AC: 24 AN: 1090782

Other (OTH) AF: 0.00204 AC: 119 AN: 58418

GnomAD4 genome AF: 0.00950 AC: 1447 AN: 152286 Hom.: 27 Cov.: 32 AF XY: 0.00924 AC XY: 688 AN XY: 74454

African (AFR) AF: 0.0339 AC: 1407 AN: 41562

American (AMR) AF: 0.00176 AC: 27 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00496 Hom.: 10

Bravo AF: 0.0109

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Emery-Dreifuss muscular dystrophy Benign:1

Jan 24, 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
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.024
DANN	Benign	0.80
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.19
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: rs138079219; hg19: chr22-39136272;