1-228211918-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_001386125.1(OBSCN):c.135G>C(p.Lys45Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000399 in 1,608,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

OBSCN
NM_001386125.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.88

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17173085).

BP6

Variant 1-228211918-G-C is Benign according to our data. Variant chr1-228211918-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1770809.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OBSCN	NM_001386125.1 linkuse as main transcript	c.135G>C	p.Lys45Asn	missense_variant	2/116	ENST00000680850.1
OBSCN-AS1	NR_073155.1 linkuse as main transcript	n.234+1504C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OBSCN	ENST00000680850.1 linkuse as main transcript	c.135G>C	p.Lys45Asn	missense_variant	2/116		NM_001386125.1	P4
OBSCN-AS1	ENST00000295012.5 linkuse as main transcript	n.239+1504C>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000295

AC:

AN:

234212

Hom.:

AF XY:

0.000318

AC XY:

AN XY:

129132

show subpopulations

Gnomad AFR exome

AF:

0.000230

Gnomad AMR exome

AF:

0.000621

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000382

Gnomad OTH exome

AF:

0.000875

GnomAD4 exome

AF:

0.000410

AC:

597

AN:

1456660

Hom.:

Cov.:

AF XY:

0.000414

AC XY:

300

AN XY:

724272

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000405

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000502

Gnomad4 OTH exome

AF:

0.000266

GnomAD4 genome

AF:

0.000295

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000425

Hom.:

Bravo

AF:

0.000295

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000486

AC:

ExAC

AF:

0.000217

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.43

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.052

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

D;D;T;.;.

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.17

T;T;T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.8

M;M;.;.;M

MutationTaster

Benign

0.79

D;D;D;D;N

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.8

D;D;D;.;.

REVEL

Uncertain

0.40

Sift

Uncertain

0.015

D;D;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;.

Polyphen

1.0

D;D;.;.;D

Vest4

0.43

MutPred

0.73

Loss of ubiquitination at K45 (P = 0.0141);Loss of ubiquitination at K45 (P = 0.0141);Loss of ubiquitination at K45 (P = 0.0141);Loss of ubiquitination at K45 (P = 0.0141);Loss of ubiquitination at K45 (P = 0.0141);

MVP

0.69

MPC

2.3

ClinPred

0.11

GERP RS

0.53

Varity_R

0.95

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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