2-219551536-C-T

Variant names:

• chr2-219551536-C-T
• rs3795991
• NM_015311.3:c.5676G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_015311.3(OBSL1):​c.5676G>A​(p.Leu1892Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000908 in 1,589,990 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00088 (17 hom.)
• Consequence: OBSL1 NM_015311.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.965

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 2-219551536-C-T is Benign according to our data. Variant chr2-219551536-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 334459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.965 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00117 (178/152352) while in subpopulation EAS AF= 0.0297 (154/5190). AF 95% confidence interval is 0.0259. There are 7 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OBSL1	NM_015311.3	c.5676G>A	p.Leu1892Leu	synonymous_variant	Exon 20 of 21	ENST00000404537.6	NP_056126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OBSL1	ENST00000404537.6	c.5676G>A	p.Leu1892Leu	synonymous_variant	Exon 20 of 21	1	NM_015311.3	ENSP00000385636.1

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152234 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0294

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00227 AC: 478 AN: 210770 Hom.: 9 AF XY: 0.00216 AC XY: 247 AN XY: 114172

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000328

Gnomad ASJ exome AF: 0.00173

Gnomad EAS exome AF: 0.0281

Gnomad SAS exome AF: 0.000641

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000216

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000880 AC: 1265 AN: 1437638 Hom.: 17 Cov.: 33 AF XY: 0.000889 AC XY: 634 AN XY: 712806

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000242

Gnomad4 ASJ exome AF: 0.00129

Gnomad4 EAS exome AF: 0.0279

Gnomad4 SAS exome AF: 0.000460

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000418

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152352 Hom.: 7 Cov.: 33 AF XY: 0.00136 AC XY: 101 AN XY: 74512

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0297

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000290 Hom.: 0

Bravo AF: 0.00142

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

3M syndrome 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3795991; hg19: chr2-220416258; COSMIC: COSV54710463; COSMIC: COSV54710463;