chr2-219550924-T-C

Variant names:

• chr2-219550924-T-C
• rs1043582
• NM_015311.3:c.5684-82A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015311.3(OBSL1):​c.5684-82A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 1,567,400 control chromosomes in the GnomAD database, including 159,017 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14883 hom., cov: 32)
  • Exomes 𝑓: 0.45 (144134 hom.)
• Consequence: OBSL1 NM_015311.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.258
• Publications: 4 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]

OBSL1 Gene-Disease associations (from GenCC):

• 3M syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 3-M syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-219550924-T-C is Benign according to our data. Variant chr2-219550924-T-C is described in ClinVar as Benign. ClinVar VariationId is 1287989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

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.5684-82A>G		intron	N/A	NP_056126.1	O75147-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSL1	ENST00000404537.6	TSL:1 MANE Select	c.5684-82A>G		intron	N/A	ENSP00000385636.1	O75147-3
	OBSL1	ENST00000953546.1		c.5696-82A>G		intron	N/A	ENSP00000623605.1
	OBSL1	ENST00000953548.1		c.5627-82A>G		intron	N/A	ENSP00000623607.1

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66531 AN: 151722 Hom.: 14874 Cov.: 32

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.483

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.362

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.410

GnomAD4 exome AF: 0.447 AC: 632284 AN: 1415560 Hom.: 144134 Cov.: 42 AF XY: 0.440 AC XY: 308303 AN XY: 700228

African (AFR) AF: 0.388 AC: 12577 AN: 32382

American (AMR) AF: 0.530 AC: 19736 AN: 37244

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 8364 AN: 25368

East Asian (EAS) AF: 0.352 AC: 13097 AN: 37206

South Asian (SAS) AF: 0.259 AC: 20970 AN: 80876

European-Finnish (FIN) AF: 0.510 AC: 25058 AN: 49116

Middle Eastern (MID) AF: 0.348 AC: 1889 AN: 5434

European-Non Finnish (NFE) AF: 0.464 AC: 505682 AN: 1089158

Other (OTH) AF: 0.424 AC: 24911 AN: 58776

GnomAD4 genome AF: 0.438 AC: 66575 AN: 151840 Hom.: 14883 Cov.: 32 AF XY: 0.440 AC XY: 32613 AN XY: 74180

African (AFR) AF: 0.402 AC: 16631 AN: 41362

American (AMR) AF: 0.483 AC: 7379 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1196 AN: 3464

East Asian (EAS) AF: 0.406 AC: 2088 AN: 5140

South Asian (SAS) AF: 0.253 AC: 1219 AN: 4822

European-Finnish (FIN) AF: 0.521 AC: 5482 AN: 10530

Middle Eastern (MID) AF: 0.366 AC: 106 AN: 290

European-Non Finnish (NFE) AF: 0.460 AC: 31235 AN: 67942

Other (OTH) AF: 0.406 AC: 857 AN: 2110

Alfa AF: 0.451 Hom.: 1983

Bravo AF: 0.437

Asia WGS AF: 0.313 AC: 1096 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.7
DANN	Benign	0.61
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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: rs1043582; hg19: chr2-220415646; COSMIC: COSV54706169; COSMIC: COSV54706169;