2-151654090-T-C

Position:

• chr2-151654090-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001164507.2(NEB):​c.6817A>G​(p.Lys2273Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000323 in 1,599,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 5.74

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-151654090-T-C is Benign according to our data. Variant chr2-151654090-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 331495.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.6817A>G	p.Lys2273Glu	missense_variant	52/182	ENST00000427231.7
NEB	NM_001164508.2	c.6817A>G	p.Lys2273Glu	missense_variant	52/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.6817A>G	p.Lys2273Glu	missense_variant	52/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.6817A>G	p.Lys2273Glu	missense_variant	52/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.6817A>G	p.Lys2273Glu	missense_variant	52/150	5

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000360 AC: 86 AN: 238940 Hom.: 0 AF XY: 0.000316 AC XY: 41 AN XY: 129702

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000126

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000800

Gnomad NFE exome AF: 0.000564

Gnomad OTH exome AF: 0.000525

GnomAD4 exome AF: 0.000326 AC: 472 AN: 1446908 Hom.: 0 Cov.: 27 AF XY: 0.000353 AC XY: 254 AN XY: 719676

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.000166

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.000904

Gnomad4 NFE exome AF: 0.000368

Gnomad4 OTH exome AF: 0.000134

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74450

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000492 Hom.: 0

Bravo AF: 0.000204

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000614 AC: 5

ExAC AF: 0.000431 AC: 52

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The NEB p.Lys2273Glu variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs199700878) and ClinVar (classified as likely benign by Invitae and uncertain significance by Illumina). The variant was identified in control databases in 103 of 270336 chromosomes (1 homozygous) at a frequency of 0.000381 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 20 of 24710 chromosomes (freq: 0.000809), Other in 5 of 6800 chromosomes (freq: 0.000735), European (non-Finnish) in 74 of 125282 chromosomes (freq: 0.000591) and Latino in 4 of 32652 chromosomes (freq: 0.000123), but was not observed in the African, Ashkenazi Jewish, East Asian, or South Asian populations. The p.Lys2273 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2021

The c.6817A>G (p.K2273E) alteration is located in exon 52 (coding exon 50) of the NEB gene. This alteration results from a A to G substitution at nucleotide position 6817, causing the lysine (K) at amino acid position 2273 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

NEB-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 25, 2023

The NEB c.6817A>G variant is predicted to result in the amino acid substitution p.Lys2273Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.081% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-152510604-T-C). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;.;T;.;T;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;.;.
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.010	D
MutationAssessor	Pathogenic	3.1	M;M;.;M;M;M;M
MutationTaster	Benign	0.88	D;D;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N;N;.;N;N;.;.
REVEL	Uncertain	0.44
Sift	Benign	0.15	T;D;.;D;T;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		0.45	.;.;.;.;B;.;.
Vest4		0.58
MVP		0.86
MPC		0.29
ClinPred		0.16	T
GERP RS		5.7
Varity_R		0.27
gMVP		0.54

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: rs199700878; hg19: chr2-152510604;