rs41270201

Positions:

• chr2-151508075-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164508.2(NEB):​c.23381C>T​(p.Ser7794Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,609,282 control chromosomes in the GnomAD database, including 531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (24 hom., cov: 33)
  • Exomes 𝑓: 0.024 (507 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 9.35

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]

NEB (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008599877).
• BP6: Variant 2-151508075-G-A is Benign according to our data. Variant chr2-151508075-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151508075-G-A is described in Lovd as [Benign]. Variant chr2-151508075-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0164 (2497/152236) while in subpopulation NFE AF= 0.027 (1838/68028). AF 95% confidence interval is 0.026. There are 24 homozygotes in gnomad4. There are 1126 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.23381C>T	p.Ser7794Leu	missense_variant	162/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.23381C>T	p.Ser7794Leu	missense_variant	162/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.23381C>T	p.Ser7794Leu	missense_variant	162/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.23381C>T	p.Ser7794Leu	missense_variant	162/182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2497 AN: 152118 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0175 AC: 4228 AN: 242286 Hom.: 50 AF XY: 0.0174 AC XY: 2280 AN XY: 131314

Gnomad AFR exome AF: 0.00484

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.00194

Gnomad EAS exome AF: 0.0000563

Gnomad SAS exome AF: 0.00133

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.0280

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0237 AC: 34500 AN: 1457046 Hom.: 507 Cov.: 30 AF XY: 0.0230 AC XY: 16637 AN XY: 724446

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.00255

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.0270

Gnomad4 NFE exome AF: 0.0281

Gnomad4 OTH exome AF: 0.0176

GnomAD4 genome AF: 0.0164 AC: 2497 AN: 152236 Hom.: 24 Cov.: 33 AF XY: 0.0151 AC XY: 1126 AN XY: 74418

Gnomad4 AFR AF: 0.00453

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0197

Gnomad4 NFE AF: 0.0270

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0244 Hom.: 81

Bravo AF: 0.0158

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00597 AC: 22

ESP6500EA AF: 0.0272 AC: 223

ExAC AF: 0.0176 AC: 2121

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

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	Dec 22, 2015	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. -
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. -
Likely 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	Jun 24, 2019	Variant summary: NEB c.23486C>T (p.Ser7829Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.017 in 242286 control chromosomes in the gnomAD database, including 50 homozygotes. The observed variant frequency is approximately 5-folds higher than 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.23486C>T in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ser7829Leu in exon 163 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 2.7% (223/8186) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs41270201). -

not provided Benign:2

Likely 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)	-	- -

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	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;.;T;.;D;T;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;.;.
MetaRNN	Benign	0.0086	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M;.;.;.;M;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.3	D;D;.;D;D;D;.;.
REVEL	Benign	0.27
Sift	Uncertain	0.020	D;T;.;T;D;T;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.;.
Vest4		0.46
MPC		0.25
ClinPred		0.0096	T
GERP RS		5.3
Varity_R		0.28
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41270201; hg19: chr2-152364589;