rs61254943

Positions:

• chr2-151576372-G-A
• chr2-151576372-G-C
• chr2-151576372-G-T

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.16705-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,566,422 control chromosomes in the GnomAD database, including 55,679 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5681 hom., cov: 27)
  • Exomes 𝑓: 0.26 (49998 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.367

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-151576372-G-A is Benign according to our data. Variant chr2-151576372-G-A is described in ClinVar as [Benign]. Clinvar id is 95105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151576372-G-A is described in Lovd as [Benign]. Variant chr2-151576372-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.16705-18C>T		intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.16705-18C>T		intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.16705-18C>T		intron_variant		5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.16705-18C>T		intron_variant		5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.11602-18C>T		intron_variant		5		ENSP00000386259
NEB	ENST00000413693.5	c.895-18C>T		intron_variant		5		ENSP00000410961

Frequencies

GnomAD3 genomes AF: 0.270 AC: 40465 AN: 149954 Hom.: 5680 Cov.: 27

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.274

GnomAD3 exomes AF: 0.273 AC: 66584 AN: 243458 Hom.: 9629 AF XY: 0.266 AC XY: 35109 AN XY: 132020

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.393

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.310

Gnomad SAS exome AF: 0.182

Gnomad FIN exome AF: 0.283

Gnomad NFE exome AF: 0.260

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.261 AC: 370262 AN: 1416366 Hom.: 49998 Cov.: 28 AF XY: 0.259 AC XY: 181952 AN XY: 702198

Gnomad4 AFR exome AF: 0.252

Gnomad4 AMR exome AF: 0.388

Gnomad4 ASJ exome AF: 0.236

Gnomad4 EAS exome AF: 0.347

Gnomad4 SAS exome AF: 0.187

Gnomad4 FIN exome AF: 0.287

Gnomad4 NFE exome AF: 0.258

Gnomad4 OTH exome AF: 0.268

GnomAD4 genome AF: 0.270 AC: 40478 AN: 150056 Hom.: 5681 Cov.: 27 AF XY: 0.272 AC XY: 19934 AN XY: 73188

Gnomad4 AFR AF: 0.249

Gnomad4 AMR AF: 0.380

Gnomad4 ASJ AF: 0.243

Gnomad4 EAS AF: 0.321

Gnomad4 SAS AF: 0.188

Gnomad4 FIN AF: 0.276

Gnomad4 NFE AF: 0.259

Gnomad4 OTH AF: 0.272

Alfa AF: 0.190 Hom.: 581

Bravo AF: 0.280

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2017	Variant summary: The NEB c.16705-18C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 32194/119748 control chromosomes (4569 homozygotes) at a frequency of 0.2688479, which is approximately 76 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), evidence that this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nemaline myopathy 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	-0.89
CADD	Benign	4.1
DANN	Benign	0.24

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: rs61254943; hg19: chr2-152432886; COSMIC: COSV51458588;