2-219565481-C-T

Position:

chr2-219565481-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 links:

OBSL1 (HGNC:):

OBSL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 334508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219565481-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
OBSL1	NM_015311.3 linkuse as main transcript	c.2168G>A	p.Arg723Lys	missense_variant	6/21	ENST00000404537.6	NP_056126.1	O75147-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OBSL1	ENST00000404537.6 linkuse as main transcript	c.2168G>A	p.Arg723Lys	missense_variant	6/21	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

GnomAD3 exomes

AF:

0.867

AC:

214295

AN:

247090

Hom.:

93670

AF XY:

0.871

AC XY:

116968

AN XY:

134248

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 SAS exome

AF:

0.835

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

Gnomad4 AFR exome

AF:

0.622

Gnomad4 AMR exome

AF:

0.836

Gnomad4 ASJ exome

AF:

0.857

Gnomad4 EAS exome

AF:

0.886

Gnomad4 SAS exome

AF:

0.838

Gnomad4 FIN exome

AF:

0.916

Gnomad4 NFE exome

AF:

0.909

Gnomad4 OTH exome

AF:

0.879

GnomAD4 genome

AF:

0.821

AC:

124942

AN:

152164

Hom.:

52394

Cov.:

AF XY:

0.822

AC XY:

61146

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.635

Gnomad4 AMR

AF:

0.834

Gnomad4 ASJ

AF:

0.862

Gnomad4 EAS

AF:

0.904

Gnomad4 SAS

AF:

0.837

Gnomad4 FIN

AF:

0.920

Gnomad4 NFE

AF:

0.904

Gnomad4 OTH

AF:

0.843

Alfa

AF:

0.872

Hom.:

46786

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

3M syndrome 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

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;.

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over