rs2288193

chr2-151492328-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):c.24874-47A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,593,840 control chromosomes in the GnomAD database, including 89,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6203 hom., cov: 31)
  • Exomes 𝑓: 0.33 (83752 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.887

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-151492328-T-A is Benign according to our data. Variant chr2-151492328-T-A is described in ClinVar as [Benign]. Clinvar id is 257804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151492328-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.24874-47A>T		intron_variant		ENST00000427231.7
NEB	NM_001164508.2	c.24874-47A>T		intron_variant		ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.24874-47A>T		intron_variant		5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.24874-47A>T		intron_variant		5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39680 AN: 151960 Hom.: 6197 Cov.: 31

Gnomad AFR AF: 0.0820

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.269

GnomAD3 exomes AF: 0.301 AC: 71191 AN: 236906 Hom.: 11488 AF XY: 0.299 AC XY: 38334 AN XY: 128192

Gnomad AFR exome AF: 0.0748

Gnomad AMR exome AF: 0.322

Gnomad ASJ exome AF: 0.249

Gnomad EAS exome AF: 0.262

Gnomad SAS exome AF: 0.207

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.350

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.335 AC: 482412 AN: 1441762 Hom.: 83752 Cov.: 30 AF XY: 0.330 AC XY: 236330 AN XY: 715206

Gnomad4 AFR exome AF: 0.0712

Gnomad4 AMR exome AF: 0.316

Gnomad4 ASJ exome AF: 0.246

Gnomad4 EAS exome AF: 0.279

Gnomad4 SAS exome AF: 0.202

Gnomad4 FIN exome AF: 0.350

Gnomad4 NFE exome AF: 0.358

Gnomad4 OTH exome AF: 0.306

GnomAD4 genome AF: 0.261 AC: 39690 AN: 152078 Hom.: 6203 Cov.: 31 AF XY: 0.261 AC XY: 19380 AN XY: 74324

Gnomad4 AFR AF: 0.0819

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.238

Gnomad4 EAS AF: 0.257

Gnomad4 SAS AF: 0.202

Gnomad4 FIN AF: 0.360

Gnomad4 NFE AF: 0.356

Gnomad4 OTH AF: 0.266

Alfa AF: 0.304 Hom.: 1366

Bravo AF: 0.248

Asia WGS AF: 0.228 AC: 793 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Nemaline myopathy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Arthrogryposis multiplex congenita 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	2.3
Dann	Benign	0.56

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: rs2288193; hg19: chr2-152348842; COSMIC: COSV50868309; COSMIC: COSV50868309;