rs149881695

Positions:

• chr2-151569306-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001164507.2(NEB):​c.17497G>A​(p.Val5833Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,613,846 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V5833A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (18 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 2.55

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064363778).
• BP6: Variant 2-151569306-C-T is Benign according to our data. Variant chr2-151569306-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252580.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=2}. Variant chr2-151569306-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00202 (308/152252) while in subpopulation SAS AF= 0.0056 (27/4822). AF 95% confidence interval is 0.00395. There are 0 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.17497G>A	p.Val5833Ile	missense_variant	110/182	ENST00000427231.7
NEB	NM_001164508.2	c.17497G>A	p.Val5833Ile	missense_variant	110/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.17497G>A	p.Val5833Ile	missense_variant	110/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.17497G>A	p.Val5833Ile	missense_variant	110/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 305 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00265

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00221 AC: 550 AN: 249108 Hom.: 3 AF XY: 0.00252 AC XY: 341 AN XY: 135136

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00585

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00237

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00290 AC: 4242 AN: 1461594 Hom.: 18 Cov.: 31 AF XY: 0.00305 AC XY: 2220 AN XY: 727096

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00591

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00298

Gnomad4 OTH exome AF: 0.00381

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74448

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.000849

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00261 Hom.: 1

Bravo AF: 0.00207

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000500 AC: 2

ESP6500EA AF: 0.00216 AC: 18

ExAC AF: 0.00228 AC: 276

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00273

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:4

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Sep 07, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 06, 2020	- -

not specified Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 20, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 19, 2022	Variant summary: NEB c.17497G>A (p.Val5833Ile) 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 0.0022 in 249108 control chromosomes, predominantly at a frequency of 0.0058 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 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 a benign polymorphism found primarily in populations of South Asian origin. c.17497G>A has been reported in the literature in individuals affected with prostate cancer as well as in controls (Karyadi_2017). The report does not provide unequivocal conclusions about association of the variant with Nemaline Myopathy 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=2) and likely benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 17, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NEB: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	.;.;T;.;T;T;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T;D;D;D;T;D;.;.
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0064	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.51	N;N;.;N;N;N;.;.
REVEL	Benign	0.10
Sift	Benign	0.064	T;T;.;T;T;T;.;.
Sift4G	Benign	0.15	T;T;T;T;T;T;T;T
Polyphen		0.54	.;.;.;.;P;.;.;.
Vest4		0.21
MVP		0.44
MPC		0.094
ClinPred		0.012	T
GERP RS		6.1
Varity_R		0.10
gMVP		0.56

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: rs149881695; hg19: chr2-152425820; COSMIC: COSV51466671;