rs10930723

Positions:

• chr2-151655264-A-C
• chr2-151655264-A-G

Variant summary

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

The NM_001164508.2(NEB):​c.6807+6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,477,502 control chromosomes in the GnomAD database, including 44,208 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (9835 hom., cov: 32)
  • Exomes 𝑓: 0.20 (34373 hom.)
• Consequence: NEB NM_001164508.2 splice_region, intron
• Scores: Splicing: ADA: 0.0001402
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.210

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=-0.9).
• BP6: Variant 2-151655264-A-C is Benign according to our data. Variant chr2-151655264-A-C is described in ClinVar as [Benign]. Clinvar id is 129756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151655264-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.6807+6T>G		splice_region_variant, intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.6807+6T>G		splice_region_variant, intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.6807+6T>G		splice_region_variant, intron_variant		5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.6807+6T>G		splice_region_variant, intron_variant		5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.6807+6T>G		splice_region_variant, intron_variant		5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45449 AN: 151888 Hom.: 9781 Cov.: 32

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.609

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.278

GnomAD3 exomes AF: 0.249 AC: 55485 AN: 223232 Hom.: 9684 AF XY: 0.245 AC XY: 29734 AN XY: 121268

Gnomad AFR exome AF: 0.602

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.257

Gnomad EAS exome AF: 0.602

Gnomad SAS exome AF: 0.357

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.196 AC: 259257 AN: 1325496 Hom.: 34373 Cov.: 20 AF XY: 0.198 AC XY: 131765 AN XY: 663884

Gnomad4 AFR exome AF: 0.603

Gnomad4 AMR exome AF: 0.150

Gnomad4 ASJ exome AF: 0.251

Gnomad4 EAS exome AF: 0.624

Gnomad4 SAS exome AF: 0.341

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.157

Gnomad4 OTH exome AF: 0.238

GnomAD4 genome AF: 0.300 AC: 45557 AN: 152006 Hom.: 9835 Cov.: 32 AF XY: 0.297 AC XY: 22083 AN XY: 74292

Gnomad4 AFR AF: 0.583

Gnomad4 AMR AF: 0.182

Gnomad4 ASJ AF: 0.258

Gnomad4 EAS AF: 0.609

Gnomad4 SAS AF: 0.336

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.286

Alfa AF: 0.203 Hom.: 1330

Bravo AF: 0.315

Asia WGS AF: 0.539 AC: 1867 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 27, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.6807+6T>G in intron 51 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 43.1% (1543/3582) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs10930723). -
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. -

Nemaline myopathy 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:3

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.6807+6T>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 4/5 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 28501/83546 control chromosomes (5084 homozygotes) at a frequency of 0.3411414, which is approximately 96 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	clinical testing	Athena Diagnostics	Mar 04, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.90
CADD	Benign	1.1
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.064
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: rs10930723; hg19: chr2-152511778; COSMIC: COSV51458593;