2-219571114-G-C

Variant names:

• chr2-219571114-G-C
• rs191256186
• NM_015311.3:c.119C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015311.3(OBSL1):​c.119C>G​(p.Pro40Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,469,716 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P40P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0089 (26 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (27 hom.)
• Consequence: OBSL1 NM_015311.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.13
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006937504).
• BP6: Variant 2-219571114-G-C is Benign according to our data. Variant chr2-219571114-G-C is described in ClinVar as Benign. ClinVar VariationId is 193381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00886 (1345/151870) while in subpopulation AFR AF = 0.0304 (1264/41514). AF 95% confidence interval is 0.0291. There are 26 homozygotes in GnomAd4. There are 665 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSL1	NM_015311.3	MANE Select	c.119C>G	p.Pro40Arg	missense	Exon 1 of 21	NP_056126.1
	OBSL1	NM_001173431.2		c.119C>G	p.Pro40Arg	missense	Exon 1 of 14	NP_001166902.1
	OBSL1	NM_001173408.2		c.119C>G	p.Pro40Arg	missense	Exon 1 of 9	NP_001166879.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSL1	ENST00000404537.6	TSL:1 MANE Select	c.119C>G	p.Pro40Arg	missense	Exon 1 of 21	ENSP00000385636.1
	OBSL1	ENST00000373873.8	TSL:1	c.119C>G	p.Pro40Arg	missense	Exon 1 of 9	ENSP00000362980.4
	OBSL1	ENST00000373876.5	TSL:5	c.119C>G	p.Pro40Arg	missense	Exon 1 of 20	ENSP00000362983.1

Frequencies

GnomAD3 genomes AF: 0.00878 AC: 1333 AN: 151762 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00368

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00862

GnomAD2 exomes AF: 0.00110 AC: 98 AN: 89174 AF XY: 0.000884

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.00112

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000103

Gnomad OTH exome AF: 0.000433

GnomAD4 exome AF: 0.000870 AC: 1146 AN: 1317846 Hom.: 27 Cov.: 36 AF XY: 0.000773 AC XY: 503 AN XY: 650912

African (AFR) AF: 0.0334 AC: 895 AN: 26816

American (AMR) AF: 0.00136 AC: 37 AN: 27284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22506

East Asian (EAS) AF: 0.00 AC: 0 AN: 29270

South Asian (SAS) AF: 0.000195 AC: 14 AN: 71650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32668

Middle Eastern (MID) AF: 0.00371 AC: 20 AN: 5392

European-Non Finnish (NFE) AF: 0.0000391 AC: 41 AN: 1047982

Other (OTH) AF: 0.00256 AC: 139 AN: 54278

GnomAD4 genome AF: 0.00886 AC: 1345 AN: 151870 Hom.: 26 Cov.: 33 AF XY: 0.00896 AC XY: 665 AN XY: 74246

African (AFR) AF: 0.0304 AC: 1264 AN: 41514

American (AMR) AF: 0.00367 AC: 56 AN: 15256

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10430

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.0000884 AC: 6 AN: 67882

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.00707 Hom.: 1

Bravo AF: 0.0103

ESP6500AA AF: 0.0201 AC: 62

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00150 AC: 166

Asia WGS AF: 0.00418 AC: 14 AN: 3360

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Oct 29, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.66
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.095	N
PhyloP100		1.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.58	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	0.94	T
Polyphen		1.0	D
Vest4		0.38
MVP		0.74
MPC		1.4
ClinPred		0.020	T
GERP RS		2.7
PromoterAI		0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.8
Varity_R		0.090
gMVP		0.20
Mutation Taster		=100/0	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: rs191256186; hg19: chr2-220435836;