rs975221378

Variant names:

• chr1-228211935-C-A
• rs975221378
• NM_001386125.1:c.152C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-228211935-C-A
• chr1-228211935-C-G
• chr1-228211935-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001386125.1(OBSCN):​c.152C>A​(p.Ala51Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. A51V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OBSCN NM_001386125.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44
• Publications: 2 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051107585).

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.152C>A	p.Ala51Glu	missense	Exon 2 of 116	NP_001373054.1	Q5VST9-7
	OBSCN	NM_001271223.3		c.152C>A	p.Ala51Glu	missense	Exon 2 of 116	NP_001258152.2
	OBSCN	NM_001098623.2		c.152C>A	p.Ala51Glu	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.152C>A	p.Ala51Glu	missense	Exon 2 of 116	ENSP00000505517.1	Q5VST9-7
	OBSCN	ENST00000636476.2	TSL:1	c.152C>A	p.Ala51Glu	missense	Exon 1 of 104	ENSP00000489816.2	A0ABB0L580
	OBSCN-AS1	ENST00000295012.5	TSL:1	n.239+1487G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454654 Hom.: 0 Cov.: 72 AF XY: 0.00 AC XY: 0 AN XY: 723144

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25896

East Asian (EAS) AF: 0.00 AC: 0 AN: 39474

South Asian (SAS) AF: 0.00 AC: 0 AN: 85016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109796

Other (OTH) AF: 0.00 AC: 0 AN: 60038

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.010	N
PhyloP100		1.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.81	N
REVEL	Benign	0.11
Sift	Benign	0.92	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.071
MutPred		0.47		Gain of disorder (P = 0.0351)
MVP		0.50
MPC		1.1
ClinPred		0.029	T
GERP RS		2.6
PromoterAI		0.013	Neutral
Varity_R		0.25
gMVP		0.55
Mutation Taster		=293/7	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: rs975221378; hg19: chr1-228399636;