2-219565481-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015311.3(OBSL1):c.2168G>A(p.Arg723Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.886 in 1,610,938 control chromosomes in the GnomAD database, including 635,987 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.82 ( 52394 hom., cov: 32)

Exomes 𝑓: 0.89 ( 583593 hom. )

Consequence

OBSL1
NM_015311.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.308

Publications

36 publications found

Variant links:

Genes affected

OBSL1 (HGNC:29092): (obscurin like cytoskeletal adaptor 1) Cytoskeletal adaptor proteins function in linking the internal cytoskeleton of cells to the cell membrane. This gene encodes a cytoskeletal adaptor protein, which is a member of the Unc-89/obscurin family. The protein contains multiple N- and C-terminal immunoglobulin (Ig)-like domains and a central fibronectin type 3 domain. Mutations in this gene cause 3M syndrome type 2. Alternatively spliced transcript variants encoding different isoforms have been found in this gene. [provided by RefSeq, Mar 2010]

OBSL1 Gene-Disease associations (from GenCC):

3M syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
3-M syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OBSL1 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=7.506006E-7).

BP6

Variant 2-219565481-C-T is Benign according to our data. Variant chr2-219565481-C-T is described in ClinVar as Benign. ClinVar VariationId is 334508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OBSL1	NM_015311.3 link	c.2168G>A	p.Arg723Lys	missense_variant	Exon 6 of 21	ENST00000404537.6	NP_056126.1	O75147-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OBSL1	ENST00000404537.6 link	c.2168G>A	p.Arg723Lys	missense_variant	Exon 6 of 21	1	NM_015311.3	ENSP00000385636.1		O75147-3

Frequencies

GnomAD3 genomes

AF:

0.821

AC:

124853

AN:

152046

Hom.:

52358

Cov.:

show subpopulations

Gnomad AFR

AF:

0.635

Gnomad AMI

AF:

0.921

Gnomad AMR

AF:

0.834

Gnomad ASJ

AF:

0.862

Gnomad EAS

AF:

0.904

Gnomad SAS

AF:

0.836

Gnomad FIN

AF:

0.920

Gnomad MID

AF:

0.820

Gnomad NFE

AF:

0.904

Gnomad OTH

AF:

0.842

GnomAD2 exomes

AF:

0.867

AC:

214295

AN:

247090

AF XY:

0.871

show subpopulations

Gnomad AFR exome

AF:

0.629

Gnomad AMR exome

AF:

0.831

Gnomad ASJ exome

AF:

0.855

Gnomad EAS exome

AF:

0.916

Gnomad FIN exome

AF:

0.920

Gnomad NFE exome

AF:

0.904

Gnomad OTH exome

AF:

0.872

GnomAD4 exome

AF:

0.893

AC:

1302647

AN:

1458774

Hom.:

583593

Cov.:

AF XY:

0.892

AC XY:

647501

AN XY:

725786

show subpopulations

African (AFR)

AF:

0.622

AC:

20809

AN:

33476

American (AMR)

AF:

0.836

AC:

37382

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.857

AC:

22398

AN:

26136

East Asian (EAS)

AF:

0.886

AC:

35185

AN:

39700

South Asian (SAS)

AF:

0.838

AC:

72297

AN:

86252

European-Finnish (FIN)

AF:

0.916

AC:

46315

AN:

50574

Middle Eastern (MID)

AF:

0.855

AC:

4931

AN:

5768

European-Non Finnish (NFE)

AF:

0.909

AC:

1010302

AN:

1111808

Other (OTH)

AF:

0.879

AC:

53028

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

7779

15557

23336

31114

38893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21432

42864

64296

85728

107160

<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:

0.821

AC:

124942

AN:

152164

Hom.:

52394

Cov.:

AF XY:

0.822

AC XY:

61146

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.635

AC:

26357

AN:

41476

American (AMR)

AF:

0.834

AC:

12744

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.862

AC:

2992

AN:

3472

East Asian (EAS)

AF:

0.904

AC:

4676

AN:

5174

South Asian (SAS)

AF:

0.837

AC:

4030

AN:

4812

European-Finnish (FIN)

AF:

0.920

AC:

9766

AN:

10612

Middle Eastern (MID)

AF:

0.816

AC:

240

AN:

294

European-Non Finnish (NFE)

AF:

0.904

AC:

61518

AN:

68014

Other (OTH)

AF:

0.843

AC:

1779

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1038

2076

3115

4153

5191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

876

1752

2628

3504

4380

<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:

0.871

Hom.:

63605

Bravo

AF:

0.808

TwinsUK

AF:

0.916

AC:

3395

ALSPAC

AF:

0.909

AC:

3504

ESP6500AA

AF:

0.672

AC:

2746

ESP6500EA

AF:

0.904

AC:

7582

ExAC

AF:

0.865

AC:

104545

Asia WGS

AF:

0.857

AC:

2981

AN:

3478

EpiCase

AF:

0.903

EpiControl

AF:

0.901

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

3M syndrome 2

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

3.4

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.0091

T;.;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.11

T;T;T;T;T

MetaRNN

Benign

7.5e-7

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.97

N;.;N;N;.

PhyloP100

-0.31

PrimateAI

Benign

0.33

PROVEAN

Benign

1.1

N;N;.;N;N

REVEL

Benign

0.049

Sift

Benign

1.0

T;T;.;T;T

Sift4G

Benign

0.93

T;T;T;T;T

Polyphen

0.0

B;.;.;B;B

Vest4

0.039

MPC

0.16

ClinPred

0.00028

GERP RS

2.1

Varity_R

0.069

gMVP

0.49

Mutation Taster

=99/1

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over