rs139004902

Positions:

• chr22-38741508-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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:):

ACMG classification

Verdict is Benign. Variant got -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 id is 461671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38741508-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUN2	NM_015374.3	c.1132G>A	p.Val378Ile	missense_variant	10/18	ENST00000689035.1	NP_056189.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUN2	ENST00000689035.1	c.1132G>A	p.Val378Ile	missense_variant	10/18		NM_015374.3	ENSP00000508608	P2
	ENST00000416406.1	n.165+2341C>T		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.00742 AC: 1862 AN: 251052 Hom.: 14 AF XY: 0.00751 AC XY: 1020 AN XY: 135790

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 SAS exome AF: 0.00376

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

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00606

Gnomad4 ASJ exome AF: 0.00972

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00437

Gnomad4 FIN exome AF: 0.0107

Gnomad4 NFE exome AF: 0.00956

Gnomad4 OTH exome AF: 0.00753

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

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.00483

Gnomad4 ASJ AF: 0.00952

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.0102

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00896 Hom.: 10

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

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;.;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.67	.;T;T
MetaRNN	Benign	0.0047	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.;M
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.47	N;N;N
REVEL	Benign	0.026
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.48	T;T;T
Polyphen		0.34	B;.;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

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: rs139004902; hg19: chr22-39137513; COSMIC: COSV99325976; COSMIC: COSV99325976;