chr1-228211967-G-C

Variant names:

• chr1-228211967-G-C
• rs1165863427
• NM_001386125.1:c.184G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001386125.1(OBSCN):​c.184G>C​(p.Gly62Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G62S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: OBSCN NM_001386125.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.80
• Publications: 0 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-AS1 (HGNC:32047): (OBSCN antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSCN	NM_001386125.1	MANE Select	c.184G>C	p.Gly62Arg	missense	Exon 2 of 116	NP_001373054.1	Q5VST9-7
	OBSCN	NM_001271223.3		c.184G>C	p.Gly62Arg	missense	Exon 2 of 116	NP_001258152.2
	OBSCN	NM_001098623.2		c.184G>C	p.Gly62Arg	missense	Exon 2 of 105	NP_001092093.2	A0ABB0I190

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSCN	ENST00000680850.1	MANE Select	c.184G>C	p.Gly62Arg	missense	Exon 2 of 116	ENSP00000505517.1	Q5VST9-7
	OBSCN	ENST00000636476.2	TSL:1	c.184G>C	p.Gly62Arg	missense	Exon 1 of 104	ENSP00000489816.2	A0ABB0L580
	OBSCN-AS1	ENST00000295012.5	TSL:1	n.239+1455C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447992 Hom.: 0 Cov.: 73 AF XY: 0.00 AC XY: 0 AN XY: 719270

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33290

American (AMR) AF: 0.00 AC: 0 AN: 43616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25766

East Asian (EAS) AF: 0.00 AC: 0 AN: 39170

South Asian (SAS) AF: 0.00 AC: 0 AN: 83952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107014

Other (OTH) AF: 0.00 AC: 0 AN: 59794

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.012	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.36
MutPred		0.76		Gain of solvent accessibility (P = 0.1014)
MVP		0.83
MPC		2.3
ClinPred		0.96	D
GERP RS		3.7
PromoterAI		-0.028	Neutral
Varity_R		0.81
gMVP		0.76
Mutation Taster		=265/35	polymorphism

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: rs1165863427; hg19: chr1-228399668;