chr1-228347383-C-T

Variant names:

• chr1-228347383-C-T
• rs374400
• NM_001386125.1:c.21020-2507C>T

Variant summary

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

The NM_001386125.1(OBSCN):​c.21020-2507C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 152,010 control chromosomes in the GnomAD database, including 12,501 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 0.40 (12501 hom., cov: 32)
• Consequence: OBSCN NM_001386125.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 1 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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OBSCN	NM_001386125.1	c.21020-2507C>T		intron_variant	Intron 86 of 115	ENST00000680850.1	NP_001373054.1
OBSCN	NM_001271223.3	c.21020-2507C>T		intron_variant	Intron 86 of 115		NP_001258152.2
OBSCN	NM_001098623.2	c.18149-2507C>T		intron_variant	Intron 75 of 104		NP_001092093.2
OBSCN	NM_052843.4	c.18149-2507C>T		intron_variant	Intron 75 of 80		NP_443075.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OBSCN	ENST00000680850.1	c.21020-2507C>T		intron_variant	Intron 86 of 115		NM_001386125.1	ENSP00000505517.1

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60804 AN: 151894 Hom.: 12500 Cov.: 32

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.389

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

GnomAD4 genome AF: 0.400 AC: 60827 AN: 152010 Hom.: 12501 Cov.: 32 AF XY: 0.399 AC XY: 29632 AN XY: 74340

African (AFR) AF: 0.372 AC: 15431 AN: 41436

American (AMR) AF: 0.389 AC: 5947 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1209 AN: 3466

East Asian (EAS) AF: 0.230 AC: 1189 AN: 5166

South Asian (SAS) AF: 0.256 AC: 1232 AN: 4820

European-Finnish (FIN) AF: 0.469 AC: 4952 AN: 10568

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.436 AC: 29630 AN: 67956

Other (OTH) AF: 0.385 AC: 814 AN: 2114

Alfa AF: 0.425 Hom.: 2826

Bravo AF: 0.390

Asia WGS AF: 0.251 AC: 877 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.23
DANN	Benign	0.54
PhyloP100		-1.1
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: rs374400; hg19: chr1-228535084; COSMIC: COSV52756061;