NM_001164507.2:c.13081G>A

Variant names:

• chr2-151603751-C-T
• rs202017360
• NM_001164507.2:c.13081G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001164507.2(NEB):​c.13081G>A​(p.Glu4361Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 151,794 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E4361E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 22)
  • Exomes 𝑓: 0.0035 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.851
• Publications: 3 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0210782).
• BP6: Variant 2-151603751-C-T is Benign according to our data. Variant chr2-151603751-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257730.

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.13081G>A	p.Glu4361Lys	missense	Exon 86 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.13081G>A	p.Glu4361Lys	missense	Exon 86 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.13081G>A	p.Glu4361Lys	missense	Exon 86 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.13081G>A	p.Glu4361Lys	missense	Exon 86 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.13081G>A	p.Glu4361Lys	missense	Exon 86 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.11601+6058G>A		intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 392 AN: 151676 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000948

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00442

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00206 AC: 326 AN: 157902 AF XY: 0.00206

Gnomad AFR exome AF: 0.000604

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.00320

Gnomad OTH exome AF: 0.00155

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00355 AC: 4932 AN: 1389958 Hom.: 3 Cov.: 32 AF XY: 0.00354 AC XY: 2428 AN XY: 685614

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

African (AFR) AF: 0.000735 AC: 23 AN: 31288

American (AMR) AF: 0.000953 AC: 34 AN: 35662

Ashkenazi Jewish (ASJ) AF: 0.0000794 AC: 2 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.00297 AC: 234 AN: 78842

European-Finnish (FIN) AF: 0.00269 AC: 133 AN: 49454

Middle Eastern (MID) AF: 0.000246 AC: 1 AN: 4070

European-Non Finnish (NFE) AF: 0.00407 AC: 4359 AN: 1071956

Other (OTH) AF: 0.00253 AC: 146 AN: 57774

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00258 AC: 392 AN: 151794 Hom.: 0 Cov.: 22 AF XY: 0.00219 AC XY: 163 AN XY: 74286

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

African (AFR) AF: 0.000945 AC: 39 AN: 41266

American (AMR) AF: 0.000915 AC: 14 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00442 AC: 300 AN: 67812

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00280 Hom.: 0

ExAC AF: 0.00405 AC: 106

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	2	-	Nemaline myopathy 2 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.83	T
PhyloP100		-0.85
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.095
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0	D
Vest4		0.32
MVP		0.62
MPC		0.29
ClinPred		0.028	T
GERP RS		0.82
gMVP		0.016
Mutation Taster		=93/7	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: rs202017360; hg19: chr2-152460265; COSMIC: COSV51170428;