rs1188722

Positions:

• chr1-228276575-T-C
• chr1-228276575-T-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.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. 13/20 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

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=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 id 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/exons	MANE	Protein	UniProt
OBSCN	NM_001386125.1	c.7471T>C	p.Phe2491Leu	missense_variant	26/116	ENST00000680850.1	NP_001373054.1
OBSCN	NM_001271223.3	c.7471T>C	p.Phe2491Leu	missense_variant	26/116		NP_001258152.2
OBSCN	NM_001098623.2	c.6346T>C	p.Phe2116Leu	missense_variant	22/105		NP_001092093.2
OBSCN	NM_052843.4	c.6346T>C	p.Phe2116Leu	missense_variant	22/81		NP_443075.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OBSCN	ENST00000680850.1	c.7471T>C	p.Phe2491Leu	missense_variant	26/116		NM_001386125.1	ENSP00000505517	P4

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

GnomAD3 exomes AF: 0.683 AC: 166080 AN: 243176 Hom.: 57407 AF XY: 0.670 AC XY: 89054 AN XY: 132848

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 SAS exome AF: 0.515

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

Gnomad4 AFR exome AF: 0.715

Gnomad4 AMR exome AF: 0.736

Gnomad4 ASJ exome AF: 0.645

Gnomad4 EAS exome AF: 0.732

Gnomad4 SAS exome AF: 0.518

Gnomad4 FIN exome AF: 0.746

Gnomad4 NFE exome AF: 0.693

Gnomad4 OTH exome AF: 0.674

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

Gnomad4 AFR AF: 0.718

Gnomad4 AMR AF: 0.711

Gnomad4 ASJ AF: 0.640

Gnomad4 EAS AF: 0.736

Gnomad4 SAS AF: 0.520

Gnomad4 FIN AF: 0.749

Gnomad4 NFE AF: 0.695

Gnomad4 OTH AF: 0.688

Alfa AF: 0.693 Hom.: 24155

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2020	This variant is associated with the following publications: (PMID: 22251166) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	- -

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
MutationTaster	Benign	0.99	P;P;P;P;P
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

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: rs1188722; hg19: chr1-228464276; COSMIC: COSV52748888; COSMIC: COSV52748888;