rs367952566

Variant names:

• chr2-219570341-G-A
• rs367952566
• NM_015311.3:c.892C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-219570341-G-A
• chr2-219570341-G-C
• chr2-219570341-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS1

The NM_015311.3(OBSL1):​c.892C>T​(p.Arg298Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,612,274 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: OBSL1 NM_015311.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.42
• Publications: 1 publications found

Genes affected

OBSL1 (HGNC:29092): (obscurin like cytoskeletal adaptor 1) Cytoskeletal adaptor proteins function in linking the internal cytoskeleton of cells to the cell membrane. This gene encodes a cytoskeletal adaptor protein, which is a member of the Unc-89/obscurin family. The protein contains multiple N- and C-terminal immunoglobulin (Ig)-like domains and a central fibronectin type 3 domain. Mutations in this gene cause 3M syndrome type 2. Alternatively spliced transcript variants encoding different isoforms have been found in this gene. [provided by RefSeq, Mar 2010]

INHA (HGNC:6065): (inhibin subunit alpha) This gene encodes a member of the TGF-beta (transforming growth factor-beta) superfamily of proteins. The encoded preproprotein is proteolytically processed to generate multiple peptide products, including the alpha subunit of the inhibin A and B protein complexes. These complexes negatively regulate follicle stimulating hormone secretion from the pituitary gland. Inhibins have also been implicated in regulating numerous cellular processes including cell proliferation, apoptosis, immune response and hormone secretion. Mutations in this gene may be associated with male infertility and premature ovarian failure in female human patients. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34696215).
• BP6: Variant 2-219570341-G-A is Benign according to our data. Variant chr2-219570341-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2062632.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000108 (158/1459928) while in subpopulation SAS AF = 0.00137 (118/86176). AF 95% confidence interval is 0.00117. There are 0 homozygotes in GnomAdExome4. There are 118 alleles in the male GnomAdExome4 subpopulation. Median coverage is 64. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015311.3. 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
	OBSL1	NM_015311.3	MANE Select	c.892C>T	p.Arg298Cys	missense	Exon 1 of 21	NP_056126.1	O75147-3
	OBSL1	NM_001173431.2		c.892C>T	p.Arg298Cys	missense	Exon 1 of 14	NP_001166902.1	O75147-4
	OBSL1	NM_001173408.2		c.892C>T	p.Arg298Cys	missense	Exon 1 of 9	NP_001166879.1	O75147-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSL1	ENST00000404537.6	TSL:1 MANE Select	c.892C>T	p.Arg298Cys	missense	Exon 1 of 21	ENSP00000385636.1	O75147-3
	OBSL1	ENST00000373873.8	TSL:1	c.892C>T	p.Arg298Cys	missense	Exon 1 of 9	ENSP00000362980.4	O75147-2
	OBSL1	ENST00000953546.1		c.892C>T	p.Arg298Cys	missense	Exon 1 of 21	ENSP00000623605.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000269 AC: 65 AN: 241392 AF XY: 0.000357

Gnomad AFR exome AF: 0.000865

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000563

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000108 AC: 158 AN: 1459928 Hom.: 0 Cov.: 64 AF XY: 0.000162 AC XY: 118 AN XY: 726192

African (AFR) AF: 0.000299 AC: 10 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39656

South Asian (SAS) AF: 0.00137 AC: 118 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52904

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111004

Other (OTH) AF: 0.000149 AC: 9 AN: 60304

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74504

African (AFR) AF: 0.000337 AC: 14 AN: 41588

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.000740 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000282 AC: 34

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.60
MVP		0.82
MPC		0.79
ClinPred		0.12	T
GERP RS		4.5
Varity_R		0.62
gMVP		0.68
Mutation Taster		=54/46	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: rs367952566; hg19: chr2-220435063;