rs116680988

chr22-38749760-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015374.3(SUN2):c.614+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,613,772 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (13 hom.)
• Consequence: SUN2 NM_015374.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00004167
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.129

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 22-38749760-G-A is Benign according to our data. Variant chr22-38749760-G-A is described in ClinVar as [Benign]. Clinvar id is 461690.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00801 (1219/152242) while in subpopulation AFR AF= 0.0277 (1150/41542). AF 95% confidence interval is 0.0264. There are 16 homozygotes in gnomad4. There are 578 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUN2	NM_015374.3	c.614+6C>T		splice_donor_region_variant, intron_variant		ENST00000689035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN2	ENST00000689035.1	c.614+6C>T		splice_donor_region_variant, intron_variant			NM_015374.3	P2

Frequencies

GnomAD3 genomes AF: 0.00801 AC: 1218 AN: 152124 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00216 AC: 540 AN: 250420 Hom.: 10 AF XY: 0.00152 AC XY: 206 AN XY: 135542

Gnomad AFR exome AF: 0.0298

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000791 AC: 1156 AN: 1461530 Hom.: 13 Cov.: 31 AF XY: 0.000678 AC XY: 493 AN XY: 727082

Gnomad4 AFR exome AF: 0.0283

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.00132

GnomAD4 genome AF: 0.00801 AC: 1219 AN: 152242 Hom.: 16 Cov.: 32 AF XY: 0.00777 AC XY: 578 AN XY: 74432

Gnomad4 AFR AF: 0.0277

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00391 Hom.: 5

Bravo AF: 0.00926

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Emery-Dreifuss muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.034
Dann	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.050
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: rs116680988; hg19: chr22-39145765;