rs117271684

chr2-151665469-A-G

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.5102T>C(p.Val1701Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00313 in 1,611,368 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (110 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 6.13

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=0.0027567446).
• BP6: Variant 2-151665469-A-G is Benign according to our data. Variant chr2-151665469-A-G is described in ClinVar as [Benign]. Clinvar id is 129745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151665469-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.5102T>C	p.Val1701Ala	missense_variant	42/182	ENST00000427231.7
NEB	NM_001164508.2	c.5102T>C	p.Val1701Ala	missense_variant	42/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.5102T>C	p.Val1701Ala	missense_variant	42/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.5102T>C	p.Val1701Ala	missense_variant	42/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.5102T>C	p.Val1701Ala	missense_variant	42/150	5

Frequencies

GnomAD3 genomes AF: 0.00427 AC: 644 AN: 150994 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.000536

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00804

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0698

Gnomad SAS AF: 0.00319

Gnomad FIN AF: 0.00810

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000517

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00880 AC: 2168 AN: 246388 Hom.: 51 AF XY: 0.00817 AC XY: 1091 AN XY: 133576

Gnomad AFR exome AF: 0.000328

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0770

Gnomad SAS exome AF: 0.00236

Gnomad FIN exome AF: 0.00688

Gnomad NFE exome AF: 0.000698

Gnomad OTH exome AF: 0.00568

GnomAD4 exome AF: 0.00301 AC: 4393 AN: 1460256 Hom.: 110 Cov.: 31 AF XY: 0.00296 AC XY: 2151 AN XY: 726258

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0654

Gnomad4 SAS exome AF: 0.00210

Gnomad4 FIN exome AF: 0.00794

Gnomad4 NFE exome AF: 0.000263

Gnomad4 OTH exome AF: 0.00552

GnomAD4 genome AF: 0.00426 AC: 643 AN: 151112 Hom.: 15 Cov.: 32 AF XY: 0.00476 AC XY: 351 AN XY: 73814

Gnomad4 AFR AF: 0.000535

Gnomad4 AMR AF: 0.00803

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0694

Gnomad4 SAS AF: 0.00319

Gnomad4 FIN AF: 0.00810

Gnomad4 NFE AF: 0.000517

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00381 Hom.: 40

Bravo AF: 0.00467

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.000484 AC: 4

ExAC AF: 0.00804 AC: 971

Asia WGS AF: 0.0250 AC: 86 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2016	- -
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	-	- -

Nemaline myopathy 2 Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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	Invitae	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 24, 2017	Variant summary: The NEB c.5102T>C (p.Val1701Ala) variant involves the alteration of a conserved nucleotide and is predicted to be benign by 2/4 in silico tools (SNPs&GO not captured due to low reliability index). This variant was found in 962/107782 control chromosomes (24 homozygotes) from ExAC, predominantly observed in the East Asian subpopulation at a frequency of 0.081239 (640/7878). This frequency is about 23 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T;T;T;T;.;.
MetaRNN	Benign	0.0028	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L;L;.;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N;N;.;N;N;.;.
REVEL	Benign	0.11
Sift	Benign	0.29	T;T;.;T;T;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		0.62	.;.;.;.;P;.;.
Vest4		0.51
MVP		0.32
MPC		0.27
ClinPred		0.038	T
GERP RS		4.8
Varity_R		0.19
gMVP		0.47

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: rs117271684; hg19: chr2-152521983; COSMIC: COSV50874194; COSMIC: COSV50874194;