rs199700878

Variant names:

• chr2-151654090-T-C
• rs199700878
• NM_001164507.2:c.6817A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001164508.2(NEB):​c.6817A>G​(p.Lys2273Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000323 in 1,599,172 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 5.74
• 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: 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-151654090-T-C is Benign according to our data. Variant chr2-151654090-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 331495.

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.6817A>G	p.Lys2273Glu	missense	Exon 52 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.6817A>G	p.Lys2273Glu	missense	Exon 52 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.6817A>G	p.Lys2273Glu	missense	Exon 52 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.6817A>G	p.Lys2273Glu	missense	Exon 52 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.6817A>G	p.Lys2273Glu	missense	Exon 52 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.6817A>G	p.Lys2273Glu	missense	Exon 52 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000360 AC: 86 AN: 238940 AF XY: 0.000316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000126

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000800

Gnomad NFE exome AF: 0.000564

Gnomad OTH exome AF: 0.000525

GnomAD4 exome AF: 0.000326 AC: 472 AN: 1446908 Hom.: 0 Cov.: 27 AF XY: 0.000353 AC XY: 254 AN XY: 719676

African (AFR) AF: 0.0000306 AC: 1 AN: 32654

American (AMR) AF: 0.000166 AC: 7 AN: 42246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25596

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83764

European-Finnish (FIN) AF: 0.000904 AC: 48 AN: 53116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.000368 AC: 407 AN: 1104650

Other (OTH) AF: 0.000134 AC: 8 AN: 59650

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74450

African (AFR) AF: 0.0000241 AC: 1 AN: 41560

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 68012

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000493 Hom.: 0

Bravo AF: 0.000204

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000614 AC: 5

ExAC AF: 0.000431 AC: 52

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.010	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.44
Sift	Benign	0.15	T
Sift4G	Uncertain	0.0030	D
Polyphen		0.45	B
Vest4		0.58
MVP		0.86
MPC		0.29
ClinPred		0.16	T
GERP RS		5.7
Varity_R		0.27
gMVP		0.54
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: rs199700878; hg19: chr2-152510604;