1-228211850-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001386125.1(OBSCN):c.67G>A(p.Val23Met) variant causes a missense change. The variant allele was found at a frequency of 0.000185 in 1,593,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: OBSCN NM_001386125.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.11

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-AS1 (HGNC:32047): (OBSCN antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21885547).
• BP6: Variant 1-228211850-G-A is Benign according to our data. Variant chr1-228211850-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2210937.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OBSCN	NM_001386125.1	c.67G>A	p.Val23Met	missense_variant	2/116	ENST00000680850.1
OBSCN-AS1	NR_073155.1	n.234+1572C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OBSCN	ENST00000680850.1	c.67G>A	p.Val23Met	missense_variant	2/116		NM_001386125.1	P4
OBSCN-AS1	ENST00000295012.5	n.239+1572C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000210 AC: 48 AN: 228492 Hom.: 0 AF XY: 0.000239 AC XY: 30 AN XY: 125502

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000423

Gnomad ASJ exome AF: 0.000110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000502

Gnomad NFE exome AF: 0.000303

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.000185 AC: 266 AN: 1441486 Hom.: 0 Cov.: 73 AF XY: 0.000223 AC XY: 159 AN XY: 713760

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000321

Gnomad4 ASJ exome AF: 0.000197

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000195

Gnomad4 NFE exome AF: 0.000212

Gnomad4 OTH exome AF: 0.000219

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74310

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000282 Hom.: 0

Bravo AF: 0.000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000208 AC: 25

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.45
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D;.;.
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.4	L;L;.;.;L
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	N;N;N;.;.
REVEL	Benign	0.11
Sift	Benign	0.26	T;T;T;.;.
Sift4G	Benign	0.11	T;T;T;T;.
Polyphen		0.94	P;P;.;.;P
Vest4		0.32
MVP		0.45
MPC		2.2
ClinPred		0.18	T
GERP RS		4.8
Varity_R		0.48
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200696787; hg19: chr1-228399551;