1-228317967-C-G

Variant names:

• chr1-228317967-C-G
• rs1188729
• NM_001386125.1:c.16796C>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001386125.1(OBSCN):​c.16796C>G​(p.Ser5599Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 1,613,792 control chromosomes in the GnomAD database, including 395,486 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41635 hom., cov: 33)
  • Exomes 𝑓: 0.69 (353851 hom.)
• Consequence: OBSCN NM_001386125.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.832

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.473093E-7).
• BP6: Variant 1-228317967-C-G is Benign according to our data. Variant chr1-228317967-C-G is described in ClinVar as [Benign]. Clinvar id is 1242422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OBSCN	NM_001386125.1	c.16796C>G	p.Ser5599Cys	missense_variant	Exon 64 of 116	ENST00000680850.1	NP_001373054.1
OBSCN	NM_001271223.3	c.16796C>G	p.Ser5599Cys	missense_variant	Exon 64 of 116		NP_001258152.2
OBSCN	NM_001098623.2	c.13925C>G	p.Ser4642Cys	missense_variant	Exon 53 of 105		NP_001092093.2
OBSCN	NM_052843.4	c.13925C>G	p.Ser4642Cys	missense_variant	Exon 53 of 81		NP_443075.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OBSCN	ENST00000680850.1	c.16796C>G	p.Ser5599Cys	missense_variant	Exon 64 of 116		NM_001386125.1	ENSP00000505517.1

Frequencies

GnomAD3 genomes AF: 0.735 AC: 111831 AN: 152048 Hom.: 41595 Cov.: 33

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.731

Gnomad ASJ AF: 0.646

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.774

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.718

GnomAD3 exomes AF: 0.695 AC: 173046 AN: 249048 Hom.: 61230 AF XY: 0.680 AC XY: 91828 AN XY: 135134

Gnomad AFR exome AF: 0.823

Gnomad AMR exome AF: 0.750

Gnomad ASJ exome AF: 0.638

Gnomad EAS exome AF: 0.728

Gnomad SAS exome AF: 0.497

Gnomad FIN exome AF: 0.770

Gnomad NFE exome AF: 0.700

Gnomad OTH exome AF: 0.688

GnomAD4 exome AF: 0.693 AC: 1013369 AN: 1461626 Hom.: 353851 Cov.: 69 AF XY: 0.686 AC XY: 498528 AN XY: 727094

Gnomad4 AFR exome AF: 0.824

Gnomad4 AMR exome AF: 0.748

Gnomad4 ASJ exome AF: 0.645

Gnomad4 EAS exome AF: 0.741

Gnomad4 SAS exome AF: 0.502

Gnomad4 FIN exome AF: 0.767

Gnomad4 NFE exome AF: 0.699

Gnomad4 OTH exome AF: 0.685

GnomAD4 genome AF: 0.736 AC: 111924 AN: 152166 Hom.: 41635 Cov.: 33 AF XY: 0.734 AC XY: 54607 AN XY: 74366

Gnomad4 AFR AF: 0.824

Gnomad4 AMR AF: 0.731

Gnomad4 ASJ AF: 0.646

Gnomad4 EAS AF: 0.737

Gnomad4 SAS AF: 0.503

Gnomad4 FIN AF: 0.774

Gnomad4 NFE AF: 0.700

Gnomad4 OTH AF: 0.713

Alfa AF: 0.680 Hom.: 9160

Bravo AF: 0.737

TwinsUK AF: 0.695 AC: 2576

ALSPAC AF: 0.694 AC: 2673

ESP6500AA AF: 0.833 AC: 3525

ESP6500EA AF: 0.702 AC: 5924

ExAC AF: 0.694 AC: 83936

Asia WGS AF: 0.605 AC: 2103 AN: 3478

EpiCase AF: 0.684

EpiControl AF: 0.682

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 18, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22251166) -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.32
DEOGEN2	Benign	0.017	.;T;.;.;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.00077	N
LIST_S2	Benign	0.10	T;T;T;.;.
MetaRNN	Benign	7.5e-7	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.66	N;N;.;.;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	2.2	N;N;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.089	T;T;.;.;.
Sift4G	Benign	0.11	T;T;T;T;.
Polyphen		0.0	B;B;.;.;B
Vest4		0.12
MPC		0.090
ClinPred		0.0026	T
GERP RS		2.6
Varity_R		0.11
gMVP		0.13

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

Other links and lift over

dbSNP: rs1188729; hg19: chr1-228505668;