1-228276575-T-C

Variant names:

• chr1-228276575-T-C
• rs1188722
• NM_001386125.1:c.7471T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001386125.1(OBSCN):​c.7471T>C​(p.Phe2491Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 1,611,320 control chromosomes in the GnomAD database, including 382,064 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37513 hom., cov: 33)
  • Exomes 𝑓: 0.69 (344551 hom.)
• Consequence: OBSCN NM_001386125.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.61
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0094252E-6).
• BP6: Variant 1-228276575-T-C is Benign according to our data. Variant chr1-228276575-T-C is described in ClinVar as Benign. ClinVar VariationId is 1226334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OBSCN	NM_001386125.1	c.7471T>C	p.Phe2491Leu	missense_variant	Exon 26 of 116	ENST00000680850.1	NP_001373054.1
OBSCN	NM_001271223.3	c.7471T>C	p.Phe2491Leu	missense_variant	Exon 26 of 116		NP_001258152.2
OBSCN	NM_001098623.2	c.6346T>C	p.Phe2116Leu	missense_variant	Exon 22 of 105		NP_001092093.2
OBSCN	NM_052843.4	c.6346T>C	p.Phe2116Leu	missense_variant	Exon 22 of 81		NP_443075.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OBSCN	ENST00000680850.1	c.7471T>C	p.Phe2491Leu	missense_variant	Exon 26 of 116		NM_001386125.1	ENSP00000505517.1

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106423 AN: 151950 Hom.: 37477 Cov.: 33

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.711

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.519

Gnomad FIN AF: 0.749

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.695

Gnomad OTH AF: 0.693

GnomAD2 exomes AF: 0.683 AC: 166080 AN: 243176 AF XY: 0.670

Gnomad AFR exome AF: 0.713

Gnomad AMR exome AF: 0.739

Gnomad ASJ exome AF: 0.637

Gnomad EAS exome AF: 0.728

Gnomad FIN exome AF: 0.747

Gnomad NFE exome AF: 0.693

Gnomad OTH exome AF: 0.676

GnomAD4 exome AF: 0.685 AC: 1000045 AN: 1459252 Hom.: 344551 Cov.: 57 AF XY: 0.679 AC XY: 492678 AN XY: 725944

African (AFR) AF: 0.715 AC: 23924 AN: 33456

American (AMR) AF: 0.736 AC: 32798 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.645 AC: 16822 AN: 26094

East Asian (EAS) AF: 0.732 AC: 29025 AN: 39658

South Asian (SAS) AF: 0.518 AC: 44645 AN: 86164

European-Finnish (FIN) AF: 0.746 AC: 38962 AN: 52212

Middle Eastern (MID) AF: 0.576 AC: 3318 AN: 5764

European-Non Finnish (NFE) AF: 0.693 AC: 769914 AN: 1111034

Other (OTH) AF: 0.674 AC: 40637 AN: 60290

GnomAD4 genome AF: 0.700 AC: 106508 AN: 152068 Hom.: 37513 Cov.: 33 AF XY: 0.699 AC XY: 51973 AN XY: 74314

African (AFR) AF: 0.718 AC: 29793 AN: 41508

American (AMR) AF: 0.711 AC: 10877 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 2219 AN: 3468

East Asian (EAS) AF: 0.736 AC: 3771 AN: 5124

South Asian (SAS) AF: 0.520 AC: 2504 AN: 4814

European-Finnish (FIN) AF: 0.749 AC: 7935 AN: 10598

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.695 AC: 47226 AN: 67948

Other (OTH) AF: 0.688 AC: 1454 AN: 2114

Alfa AF: 0.695 Hom.: 44204

Bravo AF: 0.699

TwinsUK AF: 0.691 AC: 2563

ALSPAC AF: 0.687 AC: 2647

ESP6500AA AF: 0.735 AC: 3119

ESP6500EA AF: 0.696 AC: 5899

ExAC AF: 0.678 AC: 81792

Asia WGS AF: 0.609 AC: 2120 AN: 3478

EpiCase AF: 0.678

EpiControl AF: 0.676

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

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
DANN	Benign	0.57
DEOGEN2	Benign	0.015	.;T;.;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.30	T;T;T;.;.
MetaRNN	Benign	0.0000010	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-3.0	N;N;.;.;N
PhyloP100		1.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	2.4	N;N;.;.;.
REVEL	Benign	0.16
Sift	Benign	1.0	T;T;.;.;.
Sift4G	Benign	1.0	T;T;T;T;.
Polyphen		0.0010	B;B;.;.;B
Vest4		0.080
MutPred		0.47		Gain of disorder (P = 0.0574);Gain of disorder (P = 0.0574);.;.;Gain of disorder (P = 0.0574);
MPC		0.11
ClinPred		0.0067	T
GERP RS		4.2
Varity_R		0.050
gMVP		0.14
Mutation Taster		=283/17	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: rs1188722; hg19: chr1-228464276; COSMIC: COSV52748888; COSMIC: COSV52748888;