rs34800215

chr2-151671122-C-Gchr2-151671122-C-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.4407G>C(p.Glu1469Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,613,902 control chromosomes in the GnomAD database, including 428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.027 (93 hom., cov: 32)
  • Exomes 𝑓: 0.018 (335 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0400

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 (MetaRNN=0.0029376447).
• BP6: Variant 2-151671122-C-G is Benign according to our data. Variant chr2-151671122-C-G is described in ClinVar as [Benign]. Clinvar id is 129743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151671122-C-G is described in Lovd as [Benign]. Variant chr2-151671122-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.4407G>C	p.Glu1469Asp	missense_variant	38/182	ENST00000427231.7
NEB	NM_001164508.2	c.4407G>C	p.Glu1469Asp	missense_variant	38/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.4407G>C	p.Glu1469Asp	missense_variant	38/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.4407G>C	p.Glu1469Asp	missense_variant	38/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.4407G>C	p.Glu1469Asp	missense_variant	38/150	5
NEB	ENST00000484968.1	n.259G>C		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes AF: 0.0274 AC: 4165 AN: 152168 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0535

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.0243

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0197 AC: 4922 AN: 249252 Hom.: 78 AF XY: 0.0203 AC XY: 2739 AN XY: 135218

Gnomad AFR exome AF: 0.0555

Gnomad AMR exome AF: 0.00872

Gnomad ASJ exome AF: 0.0468

Gnomad EAS exome AF: 0.00417

Gnomad SAS exome AF: 0.0300

Gnomad FIN exome AF: 0.0128

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0184 AC: 26966 AN: 1461616 Hom.: 335 Cov.: 33 AF XY: 0.0188 AC XY: 13699 AN XY: 727102

Gnomad4 AFR exome AF: 0.0527

Gnomad4 AMR exome AF: 0.00966

Gnomad4 ASJ exome AF: 0.0469

Gnomad4 EAS exome AF: 0.00184

Gnomad4 SAS exome AF: 0.0305

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.0167

Gnomad4 OTH exome AF: 0.0239

GnomAD4 genome AF: 0.0274 AC: 4176 AN: 152286 Hom.: 93 Cov.: 32 AF XY: 0.0266 AC XY: 1981 AN XY: 74460

Gnomad4 AFR AF: 0.0535

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.0432

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.0249

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.0174

Gnomad4 OTH AF: 0.0261

Alfa AF: 0.0178 Hom.: 23

Bravo AF: 0.0285

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.0479 AC: 198

ESP6500EA AF: 0.0188 AC: 158

ExAC AF: 0.0201 AC: 2427

Asia WGS AF: 0.0300 AC: 104 AN: 3478

EpiCase AF: 0.0178

EpiControl AF: 0.0202

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 01, 2019	Variant summary: NEB c.4407G>C (p.Glu1469Asp) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.02 in 277192 control chromosomes in the gnomAD database, including 91 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.4407G>C 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. -
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.Glu1469Asp in exon 38 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 4.8% (198/4134) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs34800215). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 28, 2020	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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. -

Nemaline myopathy 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Invitae	Feb 01, 2024	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;.;.
MetaRNN	Benign	0.0029	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;.;L;L;L;L
MutationTaster	Benign	0.99	D;D;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.4	N;N;.;N;N;.;.
REVEL	Benign	0.093
Sift	Benign	0.40	T;T;.;T;T;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.33
MutPred		0.24		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MPC		0.33
ClinPred		0.024	T
GERP RS		3.6
Varity_R		0.14
gMVP		0.42

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: rs34800215; hg19: chr2-152527636; COSMIC: COSV51417601;