rs199890298

Variant names:

• chr2-151548337-C-T
• rs199890298
• NM_001164507.2:c.20128G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001164508.2(NEB):​c.20128G>A​(p.Val6710Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000598 in 1,613,448 control chromosomes in the GnomAD database, including 1 homozygotes. 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). The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 1.91
• Publications: 4 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen
• autosomal dominant nebulin-related myopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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

Specifications for NEB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009875923).
• BP6: Variant 2-151548337-C-T is Benign according to our data. Variant chr2-151548337-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465532.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000696 (106/152258) while in subpopulation AMR AF = 0.00373 (57/15286). AF 95% confidence interval is 0.00295. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164508.2. 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.20128G>A	p.Val6710Ile	missense	Exon 131 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.20128G>A	p.Val6710Ile	missense	Exon 131 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.20128G>A	p.Val6710Ile	missense	Exon 131 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.20128G>A	p.Val6710Ile	missense	Exon 131 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.20128G>A	p.Val6710Ile	missense	Exon 131 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.15025G>A	p.Val5009Ile	missense	Exon 104 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.000697 AC: 106 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000651 AC: 162 AN: 248924 AF XY: 0.000659

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000523

Gnomad OTH exome AF: 0.000993

GnomAD4 exome AF: 0.000588 AC: 859 AN: 1461190 Hom.: 1 Cov.: 30 AF XY: 0.000572 AC XY: 416 AN XY: 726922

African (AFR) AF: 0.000239 AC: 8 AN: 33464

American (AMR) AF: 0.00257 AC: 115 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000622 AC: 691 AN: 1111450

Other (OTH) AF: 0.000729 AC: 44 AN: 60346

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74442

African (AFR) AF: 0.000168 AC: 7 AN: 41556

American (AMR) AF: 0.00373 AC: 57 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68024

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000719 Hom.: 0

Bravo AF: 0.000774

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000363 AC: 3

ExAC AF: 0.000521 AC: 63

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Nemaline myopathy 2 (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	NEB-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0077	T
Eigen	Benign	0.056
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.20	N
PhyloP100		1.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.052
Sift	Benign	0.34	T
Sift4G	Benign	0.58	T
Polyphen		0.0030	B
Vest4		0.25
MVP		0.21
MPC		0.059
ClinPred		0.014	T
GERP RS		5.0
Varity_R		0.054
gMVP		0.17
Mutation Taster		=100/0	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: rs199890298; hg19: chr2-152404851; COSMIC: COSV51473146;