NM_001164507.2:c.12443A>G

Variant names:

• chr2-151608564-T-C
• rs1553877721
• NM_001164507.2:c.12443A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001164507.2(NEB):​c.12443A>G​(p.Tyr4148Cys) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Y4148Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 2)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.60
• 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

ACMG classification

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

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.12443A>G	p.Tyr4148Cys	missense_variant	Exon 82 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.12443A>G	p.Tyr4148Cys	missense_variant	Exon 82 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.12443A>G	p.Tyr4148Cys	missense_variant	Exon 82 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.12443A>G	p.Tyr4148Cys	missense_variant	Exon 82 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.11601+1245A>G		intron_variant	Intron 78 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes Cov.: 2

GnomAD4 exome AF: 0.0000166 AC: 2 AN: 120302 Hom.: 0 Cov.: 0 AF XY: 0.0000160 AC XY: 1 AN XY: 62396

African (AFR) AF: 0.00 AC: 0 AN: 6084

American (AMR) AF: 0.00 AC: 0 AN: 6222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4234

East Asian (EAS) AF: 0.000105 AC: 1 AN: 9522

South Asian (SAS) AF: 0.00 AC: 0 AN: 11264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 518

European-Non Finnish (NFE) AF: 0.0000141 AC: 1 AN: 70690

Other (OTH) AF: 0.00 AC: 0 AN: 7372

GnomAD4 genome Cov.: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2

Nov 05, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine with cysteine at codon 4148 of the NEB protein (p.Tyr4148Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant occurs in a region of NEB (Exons 82-105) consisting of three highly homologous 8-exon repeat units (exons 82-89, exons 90-97, exons 98-105). Sequence variants in this region can be detected, but this assay cannot determine which of the three repeat units is affected, and zygosity is often ambiguous. All variants in this region are reported relative to the exon 82-89 repeat. This variant is not present in the population databases and has not been reported in the literature in individuals with NEB-related disease. However, it occurs in the triplicated region of NEB and the frequency data is considered unreliable. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "unavailable"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain affect on protein function. Missense variants in the NEB gene are typically not pathogenic, and there is no indication that this variant causes disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.23	.;T;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D;D;.;.
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Benign	-0.60	T
PhyloP100		7.6
PROVEAN	Uncertain	-2.6	D;.;D;.;.
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.73
MutPred		0.71		Gain of catalytic residue at T4150 (P = 0.0502);Gain of catalytic residue at T4150 (P = 0.0502);Gain of catalytic residue at T4150 (P = 0.0502);Gain of catalytic residue at T4150 (P = 0.0502);Gain of catalytic residue at T4150 (P = 0.0502);
MVP		0.57
MPC		0.38
ClinPred		0.89	D
GERP RS		3.9
gMVP		0.027
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs1553877721; hg19: chr2-152465078;