22-38736596-A-T

Position:

• chr22-38736596-A-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.2041-216T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 401,702 control chromosomes in the GnomAD database, including 19,501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (6787 hom., cov: 32)
  • Exomes 𝑓: 0.31 (12714 hom.)
• Consequence: SUN2 NM_015374.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.52

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 (BayesDel_noAF=-0.88).
• BP6: Variant 22-38736596-A-T is Benign according to our data. Variant chr22-38736596-A-T is described in ClinVar as [Benign]. Clinvar id is 1252553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUN2	NM_015374.3	c.2041-216T>A		intron_variant		ENST00000689035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN2	ENST00000689035.1	c.2041-216T>A		intron_variant			NM_015374.3	P2
	ENST00000418803.1	n.85+1782A>T		intron_variant, non_coding_transcript_variant		5
	ENST00000420118.1	n.317+1555A>T		intron_variant, non_coding_transcript_variant		5
	ENST00000609428.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44783 AN: 151810 Hom.: 6778 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.406

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.461

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.303

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.277

GnomAD4 exome AF: 0.309 AC: 77218 AN: 249772 Hom.: 12714 Cov.: 3 AF XY: 0.307 AC XY: 39447 AN XY: 128438

Gnomad4 AFR exome AF: 0.267

Gnomad4 AMR exome AF: 0.213

Gnomad4 ASJ exome AF: 0.292

Gnomad4 EAS exome AF: 0.499

Gnomad4 SAS exome AF: 0.254

Gnomad4 FIN exome AF: 0.331

Gnomad4 NFE exome AF: 0.295

Gnomad4 OTH exome AF: 0.288

GnomAD4 genome AF: 0.295 AC: 44820 AN: 151930 Hom.: 6787 Cov.: 32 AF XY: 0.296 AC XY: 21970 AN XY: 74284

Gnomad4 AFR AF: 0.271

Gnomad4 AMR AF: 0.232

Gnomad4 ASJ AF: 0.294

Gnomad4 EAS AF: 0.460

Gnomad4 SAS AF: 0.295

Gnomad4 FIN AF: 0.335

Gnomad4 NFE AF: 0.304

Gnomad4 OTH AF: 0.283

Alfa AF: 0.140 Hom.: 279

Bravo AF: 0.286

Asia WGS AF: 0.371 AC: 1290 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.3
DANN	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs138702; hg19: chr22-39132601;