NM_001164507.2:c.18862G>A

Variant names:

• chr2-151562640-C-T
• rs201886728
• NM_001164507.2:c.18862G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001164507.2(NEB):​c.18862G>A​(p.Val6288Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000777 in 1,581,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V6288F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 7.91
• Publications: 2 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.071285695).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.18862G>A	p.Val6288Ile	missense	Exon 120 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.18862G>A	p.Val6288Ile	missense	Exon 120 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.18862G>A	p.Val6288Ile	missense	Exon 120 of 183	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.18862G>A	p.Val6288Ile	missense	Exon 120 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.18862G>A	p.Val6288Ile	missense	Exon 120 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.13759G>A	p.Val4587Ile	missense	Exon 93 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 97 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000373 AC: 91 AN: 244090 AF XY: 0.000340

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.000355

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.000523

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.000791 AC: 1131 AN: 1429132 Hom.: 0 Cov.: 30 AF XY: 0.000759 AC XY: 535 AN XY: 705228

African (AFR) AF: 0.000213 AC: 7 AN: 32936

American (AMR) AF: 0.000501 AC: 22 AN: 43914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25442

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38920

South Asian (SAS) AF: 0.000253 AC: 21 AN: 83048

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.000942 AC: 1024 AN: 1087592

Other (OTH) AF: 0.000918 AC: 54 AN: 58824

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74380

African (AFR) AF: 0.000241 AC: 10 AN: 41520

American (AMR) AF: 0.00151 AC: 23 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000676 Hom.: 0

Bravo AF: 0.000484

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000245 AC: 1

ESP6500EA AF: 0.000480 AC: 4

ExAC AF: 0.000331 AC: 40

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Nemaline myopathy 2 (3)
-	3	-	not provided (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.0050
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		7.9
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.24
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.27	B
Vest4		0.28
MVP		0.46
MPC		0.13
ClinPred		0.070	T
GERP RS		5.7
Varity_R		0.17
gMVP		0.18
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201886728; hg19: chr2-152419154; COSMIC: COSV99430482;