rs1429486273

Variant names:

• chr2-151604642-C-T
• rs1429486273
• NM_001164507.2:c.12977G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001164507.2(NEB):​c.12977G>A​(p.Arg4326His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4326C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 4)
  • Exomes 𝑓: 0.000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -2.17
• Publications: 1 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31209314).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.12977G>A	p.Arg4326His	missense	Exon 85 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.12977G>A	p.Arg4326His	missense	Exon 85 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.12977G>A	p.Arg4326His	missense	Exon 85 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.12977G>A	p.Arg4326His	missense	Exon 85 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.12977G>A	p.Arg4326His	missense	Exon 85 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.11601+5167G>A		intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes Cov.: 4

GnomAD2 exomes AF: 0.0000205 AC: 1 AN: 48748 AF XY: 0.0000402

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000102 AC: 4 AN: 391224 Hom.: 0 Cov.: 0 AF XY: 0.0000195 AC XY: 4 AN XY: 205342

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 9944

American (AMR) AF: 0.00 AC: 0 AN: 16194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12084

East Asian (EAS) AF: 0.00 AC: 0 AN: 26402

South Asian (SAS) AF: 0.000102 AC: 4 AN: 39406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 238408

Other (OTH) AF: 0.00 AC: 0 AN: 22660

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0295860), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 4

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2

Nov 11, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 21, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.81	T
PhyloP100		-2.2
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.10
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Vest4		0.18
MutPred		0.61		Loss of catalytic residue at R4326 (P = 0.0118)
MVP		0.72
MPC		0.34
ClinPred		0.55	D
GERP RS		0.72
gMVP		0.013
Mutation Taster		=94/6	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: rs1429486273; hg19: chr2-152461156;