rs16830090

Positions:

• chr2-151485967-A-G

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.25405-34T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,604,622 control chromosomes in the GnomAD database, including 67,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5585 hom., cov: 32)
  • Exomes 𝑓: 0.29 (61695 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.158

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=-0.75).
• BP6: Variant 2-151485967-A-G is Benign according to our data. Variant chr2-151485967-A-G is described in ClinVar as [Benign]. Clinvar id is 257806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151485967-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.25405-34T>C		intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.25405-34T>C		intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.25405-34T>C		intron_variant		5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.25405-34T>C		intron_variant		5	NM_001164507.2	ENSP00000416578	A2

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38951 AN: 151970 Hom.: 5589 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.267

GnomAD3 exomes AF: 0.295 AC: 71995 AN: 243702 Hom.: 11174 AF XY: 0.292 AC XY: 38667 AN XY: 132492

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.403

Gnomad ASJ exome AF: 0.299

Gnomad EAS exome AF: 0.324

Gnomad SAS exome AF: 0.233

Gnomad FIN exome AF: 0.329

Gnomad NFE exome AF: 0.290

Gnomad OTH exome AF: 0.316

GnomAD4 exome AF: 0.287 AC: 417081 AN: 1452534 Hom.: 61695 Cov.: 28 AF XY: 0.286 AC XY: 206817 AN XY: 722878

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.397

Gnomad4 ASJ exome AF: 0.299

Gnomad4 EAS exome AF: 0.352

Gnomad4 SAS exome AF: 0.239

Gnomad4 FIN exome AF: 0.327

Gnomad4 NFE exome AF: 0.286

Gnomad4 OTH exome AF: 0.291

GnomAD4 genome AF: 0.256 AC: 38975 AN: 152088 Hom.: 5585 Cov.: 32 AF XY: 0.262 AC XY: 19465 AN XY: 74328

Gnomad4 AFR AF: 0.135

Gnomad4 AMR AF: 0.375

Gnomad4 ASJ AF: 0.301

Gnomad4 EAS AF: 0.332

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.323

Gnomad4 NFE AF: 0.285

Gnomad4 OTH AF: 0.265

Alfa AF: 0.281 Hom.: 3243

Bravo AF: 0.257

Asia WGS AF: 0.244 AC: 849 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.75
CADD	Benign	1.4
DANN	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs16830090; hg19: chr2-152342481; COSMIC: COSV50873335; COSMIC: COSV50873335;