chr1-228212510-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_001386125.1(OBSCN):c.727G>C(p.Gly243Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,604,568 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 2 hom. )

Consequence

OBSCN
NM_001386125.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.60

Variant links:

Genes affected

OBSCN (HGNC:15719): (obscurin, cytoskeletal calmodulin and titin-interacting RhoGEF) The obscurin gene spans more than 150 kb, contains over 80 exons and encodes a protein of approximately 720 kDa. The encoded protein contains 68 Ig domains, 2 fibronectin domains, 1 calcium/calmodulin-binding domain, 1 RhoGEF domain with an associated PH domain, and 2 serine-threonine kinase domains. This protein belongs to the family of giant sacromeric signaling proteins that includes titin and nebulin, and may have a role in the organization of myofibrils during assembly and may mediate interactions between the sarcoplasmic reticulum and myofibrils. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

OBSCN links:

OBSCN-AS1 (HGNC:32047): (OBSCN antisense RNA 1)

OBSCN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021728784).

BP6

Variant 1-228212510-G-C is Benign according to our data. Variant chr1-228212510-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225073.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OBSCN	NM_001386125.1 link	c.727G>C	p.Gly243Arg	missense_variant	Exon 2 of 116	ENST00000680850.1	NP_001373054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OBSCN	ENST00000680850.1 link	c.727G>C	p.Gly243Arg	missense_variant	Exon 2 of 116		NM_001386125.1	ENSP00000505517.1		A0A7P0Z489

Frequencies

GnomAD3 genomes

AF:

0.00115

AC:

174

AN:

151862

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000380

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00222

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.00101

AC:

231

AN:

228204

Hom.:

AF XY:

0.00105

AC XY:

133

AN XY:

126668

show subpopulations

Gnomad AFR exome

AF:

0.000291

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.000836

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000728

Gnomad NFE exome

AF:

0.00196

Gnomad OTH exome

AF:

0.000873

GnomAD4 exome

AF:

0.00173

AC:

2517

AN:

1452592

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

1188

AN XY:

722718

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.000961

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000623

Gnomad4 NFE exome

AF:

0.00215

Gnomad4 OTH exome

AF:

0.000931

GnomAD4 genome

AF:

0.00114

AC:

174

AN:

151976

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000380

Gnomad4 NFE

AF:

0.00222

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.00165

Hom.:

Bravo

AF:

0.000979

ExAC

AF:

0.000933

AC:

111

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Overall WES conclusion for patient, including all identified alterations: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected -

not provided

Benign:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OBSCN: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.020

.;T;.;.;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.80

T;T;T;.;.

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.022

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.29

N;N;.;.;N

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.5

N;N;N;.;.

REVEL

Benign

0.083

Sift

Benign

0.28

T;T;T;.;.

Sift4G

Benign

0.076

T;D;D;D;.

Polyphen

0.63

P;P;.;.;P

Vest4

0.31

MutPred

0.40

Gain of MoRF binding (P = 0.0411);Gain of MoRF binding (P = 0.0411);Gain of MoRF binding (P = 0.0411);Gain of MoRF binding (P = 0.0411);Gain of MoRF binding (P = 0.0411);

MVP

0.69

MPC

2.3

ClinPred

0.015

GERP RS

2.3

Varity_R

0.11

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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