dbSNP rs142011077: SUN1:p.Trp246Cys (chr7-851463-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001130965.3(SUN1):c.738G>T(p.Trp246Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00717 in 1,607,702 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0073 ( 115 hom. )

Consequence

SUN1
NM_001130965.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.23

Publications

13 publications found

Variant links:

Genes affected

SUN1 (HGNC:18587): (Sad1 and UNC84 domain containing 1) This gene is a member of the unc-84 homolog family and encodes a nuclear envelope protein with an Unc84 (SUN) domain. The protein is involved in nuclear anchorage and migration. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2019]

SUN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006855428).

BP6

Variant 7-851463-G-T is Benign according to our data. Variant chr7-851463-G-T is described in ClinVar as Benign. ClinVar VariationId is 461666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00572 (871/152324) while in subpopulation SAS AF = 0.0216 (104/4824). AF 95% confidence interval is 0.0182. There are 3 homozygotes in GnomAd4. There are 421 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130965.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SUN1	NM_001130965.3	MANE Select	c.738G>T	p.Trp246Cys	missense	Exon 6 of 19	NP_001124437.1	O94901-8
SUN1	NM_001367651.1		c.1152G>T	p.Trp384Cys	missense	Exon 9 of 22	NP_001354580.1
SUN1	NM_001367705.1		c.1131G>T	p.Trp377Cys	missense	Exon 10 of 23	NP_001354634.1	O94901-9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SUN1	ENST00000401592.6	TSL:1 MANE Select	c.738G>T	p.Trp246Cys	missense	Exon 6 of 19	ENSP00000384015.1	O94901-8
SUN1	ENST00000429178.5	TSL:1	c.513G>T	p.Trp171Cys	missense	Exon 4 of 17	ENSP00000409909.1	H0Y742
SUN1	ENST00000963118.1		c.1131G>T	p.Trp377Cys	missense	Exon 10 of 24	ENSP00000633177.1

Frequencies

GnomAD3 genomes

AF:

0.00575

AC:

875

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0222

Gnomad FIN

AF:

0.00706

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00725

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00791

AC:

1864

AN:

235506

AF XY:

0.00908

show subpopulations

Gnomad AFR exome

AF:

0.00114

Gnomad AMR exome

AF:

0.00292

Gnomad ASJ exome

AF:

0.0148

Gnomad EAS exome

AF:

0.0000578

Gnomad FIN exome

AF:

0.00715

Gnomad NFE exome

AF:

0.00702

Gnomad OTH exome

AF:

0.00776

GnomAD4 exome

AF:

0.00732

AC:

10656

AN:

1455378

Hom.:

115

Cov.:

AF XY:

0.00802

AC XY:

5802

AN XY:

723234

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

33414

American (AMR)

AF:

0.00304

AC:

133

AN:

43806

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

388

AN:

25952

East Asian (EAS)

AF:

0.00

AC:

AN:

39536

South Asian (SAS)

AF:

0.0239

AC:

2029

AN:

84778

European-Finnish (FIN)

AF:

0.00702

AC:

372

AN:

52960

Middle Eastern (MID)

AF:

0.0299

AC:

172

AN:

5758

European-Non Finnish (NFE)

AF:

0.00631

AC:

7001

AN:

1109064

Other (OTH)

AF:

0.00867

AC:

521

AN:

60110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

542

1085

1627

2170

2712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

256

512

768

1024

1280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00572

AC:

871

AN:

152324

Hom.:

Cov.:

AF XY:

0.00565

AC XY:

421

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00188

AC:

AN:

41568

American (AMR)

AF:

0.00379

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0216

AC:

104

AN:

4824

European-Finnish (FIN)

AF:

0.00706

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00725

AC:

493

AN:

68032

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00705

Hom.:

Bravo

AF:

0.00495

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.000957

AC:

ESP6500EA

AF:

0.00740

AC:

ExAC

AF:

0.00789

AC:

951

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Emery-Dreifuss muscular dystrophy (1)

not provided (1)

SUN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.089

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0069

MetaSVM

Benign

-0.73

PhyloP100

3.2

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-7.6

REVEL

Uncertain

0.41

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Vest4

0.82

MVP

0.31

MPC

0.57

ClinPred

0.026

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.68

Mutation Taster

=68/32

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over