1-228344451-T-G

Variant names:

• chr1-228344451-T-G
• rs369252
• NM_001386125.1:c.21019+2219T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001386125.1(OBSCN):​c.21019+2219T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.741 in 152,202 control chromosomes in the GnomAD database, including 42,300 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.74 (42300 hom., cov: 35)
• Consequence: OBSCN NM_001386125.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• rhabdomyolysis, susceptibility to, 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386125.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSCN	NM_001386125.1	MANE Select	c.21019+2219T>G		intron	N/A	NP_001373054.1
	OBSCN	NM_001271223.3		c.21019+2219T>G		intron	N/A	NP_001258152.2
	OBSCN	NM_001098623.2		c.18148+2219T>G		intron	N/A	NP_001092093.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSCN	ENST00000680850.1	MANE Select	c.21019+2219T>G		intron	N/A	ENSP00000505517.1
	OBSCN	ENST00000636476.2	TSL:1	c.18151+2219T>G		intron	N/A	ENSP00000489816.2
	OBSCN	ENST00000570156.7	TSL:5	c.21019+2219T>G		intron	N/A	ENSP00000455507.2

Frequencies

GnomAD3 genomes AF: 0.741 AC: 112655 AN: 152084 Hom.: 42252 Cov.: 35

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.651

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.774

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.720

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.741 AC: 112756 AN: 152202 Hom.: 42300 Cov.: 35 AF XY: 0.740 AC XY: 55079 AN XY: 74406

African (AFR) AF: 0.840 AC: 34897 AN: 41528

American (AMR) AF: 0.732 AC: 11200 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.651 AC: 2260 AN: 3472

East Asian (EAS) AF: 0.736 AC: 3815 AN: 5180

South Asian (SAS) AF: 0.526 AC: 2537 AN: 4826

European-Finnish (FIN) AF: 0.774 AC: 8203 AN: 10592

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.700 AC: 47578 AN: 67988

Other (OTH) AF: 0.714 AC: 1506 AN: 2108

Alfa AF: 0.733 Hom.: 5111

Bravo AF: 0.742

Asia WGS AF: 0.616 AC: 2144 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.77
DANN	Benign	0.45
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.97
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs369252; hg19: chr1-228532152;