22-38742327-G-T

Position:

• chr22-38742327-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015374.3(SUN2):​c.1042C>A​(p.Arg348Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,496 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R348C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SUN2 NM_015374.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.99

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUN2	NM_015374.3	c.1042C>A	p.Arg348Ser	missense_variant	9/18	ENST00000689035.1	NP_056189.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUN2	ENST00000689035.1	c.1042C>A	p.Arg348Ser	missense_variant	9/18		NM_015374.3	ENSP00000508608	P2
	ENST00000416406.1	n.165+3160G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249838 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453496 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721274

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	T;.;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	.;T;T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.;M
MutationTaster	Benign	0.11	P;P;P;P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.029	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.92	P;.;P
Vest4		0.46
MutPred		0.27		Gain of phosphorylation at R348 (P = 0.0094);.;Gain of phosphorylation at R348 (P = 0.0094);
MVP		0.65
MPC		0.60
ClinPred		0.83	D
GERP RS		5.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.33
gMVP		0.38

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: rs138708; hg19: chr22-39138332;