22-38751341-C-T

Variant names:

• chr22-38751341-C-T
• rs4510314
• NM_015374.3:c.155G>A

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.155G>A​(p.Arg52His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000807 in 1,613,940 control chromosomes in the GnomAD database, including 10 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R52C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (4 hom.)
• Consequence: SUN2 NM_015374.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.61

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042749345).
• BP6: Variant 22-38751341-C-T is Benign according to our data. Variant chr22-38751341-C-T is described in ClinVar as [Benign]. Clinvar id is 461678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUN2	NM_015374.3	c.155G>A	p.Arg52His	missense_variant	Exon 3 of 18	ENST00000689035.1	NP_056189.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUN2	ENST00000689035.1	c.155G>A	p.Arg52His	missense_variant	Exon 3 of 18		NM_015374.3	ENSP00000508608.1

Frequencies

GnomAD3 genomes AF: 0.00446 AC: 679 AN: 152156 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00114 AC: 285 AN: 251080 Hom.: 2 AF XY: 0.000811 AC XY: 110 AN XY: 135718

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000427 AC: 624 AN: 1461666 Hom.: 4 Cov.: 32 AF XY: 0.000378 AC XY: 275 AN XY: 727110

Gnomad4 AFR exome AF: 0.0150

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.00446 AC: 679 AN: 152274 Hom.: 6 Cov.: 33 AF XY: 0.00430 AC XY: 320 AN XY: 74438

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000781 Hom.: 0

Bravo AF: 0.00479

ESP6500AA AF: 0.0159 AC: 70

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00137 AC: 166

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	T;.;T;.;.;.;.;.;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.87	.;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0043	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;L;.;.;.;.;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.16	N;N;N;N;N;D;D;D;D;D
REVEL	Benign	0.086
Sift	Benign	0.29	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;.;.;.;T;.;.
Polyphen		0.14	B;.;B;.;.;.;.;.;.;.
Vest4		0.34
MVP		0.48
MPC		0.35
ClinPred		0.0055	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.33

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: rs4510314; hg19: chr22-39147346;