2-151640574-G-A

Position:

• chr2-151640574-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001164508.2(NEB):​c.8466C>T​(p.His2822His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,613,806 control chromosomes in the GnomAD database, including 458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (63 hom., cov: 32)
  • Exomes 𝑓: 0.019 (395 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.48

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-151640574-G-A is Benign according to our data. Variant chr2-151640574-G-A is described in ClinVar as [Benign]. Clinvar id is 129759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151640574-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0247 (3755/152116) while in subpopulation SAS AF= 0.0455 (219/4816). AF 95% confidence interval is 0.0405. There are 63 homozygotes in gnomad4. There are 1832 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 63 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.8466C>T	p.His2822His	synonymous_variant	61/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.8466C>T	p.His2822His	synonymous_variant	61/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.8466C>T	p.His2822His	synonymous_variant	61/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.8466C>T	p.His2822His	synonymous_variant	61/182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.8466C>T	p.His2822His	synonymous_variant	61/150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3744 AN: 151998 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0415

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.00444

Gnomad SAS AF: 0.0446

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0273

GnomAD3 exomes AF: 0.0211 AC: 5256 AN: 249214 Hom.: 81 AF XY: 0.0223 AC XY: 3008 AN XY: 135190

Gnomad AFR exome AF: 0.0462

Gnomad AMR exome AF: 0.00857

Gnomad ASJ exome AF: 0.0467

Gnomad EAS exome AF: 0.00406

Gnomad SAS exome AF: 0.0459

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0192 AC: 27994 AN: 1461690 Hom.: 395 Cov.: 32 AF XY: 0.0200 AC XY: 14566 AN XY: 727130

Gnomad4 AFR exome AF: 0.0456

Gnomad4 AMR exome AF: 0.00953

Gnomad4 ASJ exome AF: 0.0468

Gnomad4 EAS exome AF: 0.00186

Gnomad4 SAS exome AF: 0.0473

Gnomad4 FIN exome AF: 0.0124

Gnomad4 NFE exome AF: 0.0165

Gnomad4 OTH exome AF: 0.0243

GnomAD4 genome AF: 0.0247 AC: 3755 AN: 152116 Hom.: 63 Cov.: 32 AF XY: 0.0246 AC XY: 1832 AN XY: 74346

Gnomad4 AFR AF: 0.0415

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.0427

Gnomad4 EAS AF: 0.00445

Gnomad4 SAS AF: 0.0455

Gnomad4 FIN AF: 0.0123

Gnomad4 NFE AF: 0.0173

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0181 Hom.: 11

Bravo AF: 0.0250

Asia WGS AF: 0.0410 AC: 142 AN: 3478

EpiCase AF: 0.0178

EpiControl AF: 0.0200

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.His2822His in exon 61 of NEB: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 4.1% (162/3930) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs61730771). -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 01, 2019	Variant summary: NEB c.8466C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.021 in 277116 control chromosomes in the gnomAD database, including 92 homozygotes. The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in NEB causing Nemaline Myopathy 2 phenotype (0.0035), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.8466C>T in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 04, 2019	- -

Nemaline myopathy 2 Benign:3

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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.68
DANN	Benign	0.50

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: rs61730771; hg19: chr2-152497088; COSMIC: COSV51417544;