chr2-151540344-A-C

Variant names:

• chr2-151540344-A-C
• rs1553694845
• NM_001164507.2:c.20892T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001164507.2(NEB):​c.20892T>G​(p.Asp6964Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEB NM_001164507.2 missense
• Scores: Splicing: ADA: 0.00009332
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.56
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124906081 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.20892T>G	p.Asp6964Glu	missense_variant	Exon 138 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.20892T>G	p.Asp6964Glu	missense_variant	Exon 138 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.20892T>G	p.Asp6964Glu	missense_variant	Exon 138 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.20892T>G	p.Asp6964Glu	missense_variant	Exon 138 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

May 11, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy 2 Uncertain:1

Feb 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 6964 of the NEB protein (p.Asp6964Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 445892). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.049	.;.;T;.;T;T;.;.;.
Eigen	Benign	-0.023
Eigen_PC	Benign	-0.041
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T;T;T;D;T;D;.;.;T
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L;.;.;.;L;.;.;.;.
PhyloP100		1.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	N;N;.;N;N;N;.;.;N
REVEL	Uncertain	0.31
Sift	Benign	0.14	T;D;.;D;T;T;.;.;T
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;.
Polyphen		1.0	.;.;.;.;D;.;.;.;.
Vest4		0.61
MutPred		0.57		Gain of methylation at K5267 (P = 0.1451);.;.;.;Gain of methylation at K5267 (P = 0.1451);.;.;.;.;
MVP		0.54
MPC		0.34
ClinPred		0.95	D
GERP RS		1.7
Varity_R		0.10
gMVP		0.41
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000093
dbscSNV1_RF	Benign	0.36
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

Other links and lift over

dbSNP: rs1553694845; hg19: chr2-152396858;