22-38748782-G-T

Position:

• chr22-38748782-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015374.3(SUN2):​c.616C>A​(p.Arg206Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,614,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: SUN2 NM_015374.3 missense, splice_region
• Scores: Splicing: ADA: 0.008131
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057954907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUN2	NM_015374.3	c.616C>A	p.Arg206Ser	missense_variant, splice_region_variant	7/18	ENST00000689035.1	NP_056189.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUN2	ENST00000689035.1	c.616C>A	p.Arg206Ser	missense_variant, splice_region_variant	7/18		NM_015374.3	ENSP00000508608	P2
	ENST00000416406.1	n.241G>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000220

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251146 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135764

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000245 AC: 358 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.000257 AC XY: 187 AN XY: 727232

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000305

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74486

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000261 Hom.: 0

Bravo AF: 0.000155

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Emery-Dreifuss muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 14, 2023

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 206 of the SUN2 protein (p.Arg206Ser). This variant is present in population databases (rs150381950, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SUN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 577102). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.036	T;.;T;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.71	.;T;T;T;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.058	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.;M;.;.
MutationTaster	Benign	0.98	N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.51	N;N;N;N;.
REVEL	Benign	0.069
Sift	Benign	0.52	T;T;T;T;.
Sift4G	Benign	0.62	T;T;T;T;.
Polyphen		0.090	B;.;B;.;.
Vest4		0.24
MVP		0.38
MPC		0.31
ClinPred		0.046	T
GERP RS		3.7
Varity_R		0.096
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0081
dbscSNV1_RF	Benign	0.084
SpliceAI score (max)		0.030		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: rs150381950; hg19: chr22-39144787;