rs143123053

Variant names:

• chr2-151687453-A-G
• rs143123053
• NM_001164507.2:c.2603T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164508.2(NEB):​c.2603T>C​(p.Leu868Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,614,038 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L868L) has been classified as Likely benign. The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (18 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.97
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030873865).
• BP6: Variant 2-151687453-A-G is Benign according to our data. Variant chr2-151687453-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 465592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00103 (157/152354) while in subpopulation EAS AF = 0.01 (52/5188). AF 95% confidence interval is 0.00785. There are 0 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 AD,AR gene

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.2603T>C	p.Leu868Pro	missense	Exon 27 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.2603T>C	p.Leu868Pro	missense	Exon 27 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.2603T>C	p.Leu868Pro	missense	Exon 27 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.2603T>C	p.Leu868Pro	missense	Exon 27 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.2603T>C	p.Leu868Pro	missense	Exon 27 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.2603T>C	p.Leu868Pro	missense	Exon 27 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00621

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00156 AC: 389 AN: 249214 AF XY: 0.00132

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00467

Gnomad EAS exome AF: 0.00812

Gnomad FIN exome AF: 0.00562

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00117 AC: 1716 AN: 1461684 Hom.: 18 Cov.: 31 AF XY: 0.00119 AC XY: 867 AN XY: 727120

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 120 AN: 26136

East Asian (EAS) AF: 0.0223 AC: 886 AN: 39698

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86256

European-Finnish (FIN) AF: 0.00517 AC: 276 AN: 53402

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000249 AC: 277 AN: 1111848

Other (OTH) AF: 0.00104 AC: 63 AN: 60372

GnomAD4 genome AF: 0.00103 AC: 157 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74512

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.0100 AC: 52 AN: 5188

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00621 AC: 66 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.000631

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000720 AC: 6

ExAC AF: 0.00149 AC: 180

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.35
Sift	Benign	0.030	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.96
MVP		0.71
MPC		0.42
ClinPred		0.052	T
GERP RS		5.5
Varity_R		0.74
gMVP		0.59
Mutation Taster		=97/3	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: rs143123053; hg19: chr2-152543967;