rs62639696

Variant names:

• chr22-38750260-G-A
• rs62639696
• NM_015374.3:c.485C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_015374.3(SUN2):​c.485C>T​(p.Ala162Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000824 in 1,613,740 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A162A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0042 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (7 hom.)
• Consequence: SUN2 NM_015374.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00600
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 22-38750260-G-A is Benign according to our data. Variant chr22-38750260-G-A is described in ClinVar as Benign. ClinVar VariationId is 461688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000469 (686/1461404) while in subpopulation AFR AF = 0.0175 (585/33478). AF 95% confidence interval is 0.0163. There are 7 homozygotes in GnomAdExome4. There are 306 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015374.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN2	NM_015374.3	MANE Select	c.485C>T	p.Ala162Val	missense	Exon 5 of 18	NP_056189.1	Q9UH99-1
	SUN2	NM_001394427.1		c.485C>T	p.Ala162Val	missense	Exon 5 of 19	NP_001381356.1
	SUN2	NM_001199579.2		c.548C>T	p.Ala183Val	missense	Exon 5 of 18	NP_001186508.1	Q9UH99-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN2	ENST00000689035.1	MANE Select	c.485C>T	p.Ala162Val	missense	Exon 5 of 18	ENSP00000508608.1	Q9UH99-1
	SUN2	ENST00000405018.5	TSL:1	c.548C>T	p.Ala183Val	missense	Exon 5 of 18	ENSP00000385616.1	Q9UH99-2
	SUN2	ENST00000405510.5	TSL:1	c.485C>T	p.Ala162Val	missense	Exon 6 of 19	ENSP00000385740.1	Q9UH99-1

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 641 AN: 152218 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00117 AC: 294 AN: 250906 AF XY: 0.000899

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000469 AC: 686 AN: 1461404 Hom.: 7 Cov.: 32 AF XY: 0.000421 AC XY: 306 AN XY: 726974

African (AFR) AF: 0.0175 AC: 585 AN: 33478

American (AMR) AF: 0.000335 AC: 15 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53114

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111850

Other (OTH) AF: 0.000861 AC: 52 AN: 60392

GnomAD4 genome AF: 0.00422 AC: 643 AN: 152336 Hom.: 7 Cov.: 32 AF XY: 0.00420 AC XY: 313 AN XY: 74492

African (AFR) AF: 0.0151 AC: 627 AN: 41576

American (AMR) AF: 0.000653 AC: 10 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00209 Hom.: 5

Bravo AF: 0.00507

ESP6500AA AF: 0.0184 AC: 81

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00144 AC: 175

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Emery-Dreifuss muscular dystrophy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.85
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L
PhyloP100		-0.0060
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.052
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.17
MVP		0.13
MPC		0.24
ClinPred		0.0012	T
GERP RS		-0.61
Varity_R		0.012
gMVP		0.32
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.61		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs62639696; hg19: chr22-39146265;