rs13013209

Variant names:

• chr2-151643935-C-G
• rs13013209
• NM_001164507.2:c.7839G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164508.2(NEB):​c.7839G>C​(p.Lys2613Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 1,613,728 control chromosomes in the GnomAD database, including 170,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2613Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.35 (11467 hom., cov: 31)
  • Exomes 𝑓: 0.46 (158922 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.39
• Publications: 29 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, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031203926).
• BP6: Variant 2-151643935-C-G is Benign according to our data. Variant chr2-151643935-C-G is described in ClinVar as Benign. ClinVar VariationId is 95137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

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.7839G>C	p.Lys2613Asn	missense	Exon 57 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.7839G>C	p.Lys2613Asn	missense	Exon 57 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.7839G>C	p.Lys2613Asn	missense	Exon 57 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.7839G>C	p.Lys2613Asn	missense	Exon 57 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.7839G>C	p.Lys2613Asn	missense	Exon 57 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.7839G>C	p.Lys2613Asn	missense	Exon 57 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53281 AN: 151906 Hom.: 11472 Cov.: 31

Gnomad AFR AF: 0.0921

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.366

GnomAD2 exomes AF: 0.420 AC: 104730 AN: 249250 AF XY: 0.424

Gnomad AFR exome AF: 0.0824

Gnomad AMR exome AF: 0.463

Gnomad ASJ exome AF: 0.389

Gnomad EAS exome AF: 0.283

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.483

Gnomad OTH exome AF: 0.424

GnomAD4 exome AF: 0.459 AC: 671392 AN: 1461704 Hom.: 158922 Cov.: 118 AF XY: 0.458 AC XY: 332975 AN XY: 727132

African (AFR) AF: 0.0758 AC: 2539 AN: 33480

American (AMR) AF: 0.456 AC: 20394 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 10129 AN: 26136

East Asian (EAS) AF: 0.274 AC: 10887 AN: 39700

South Asian (SAS) AF: 0.387 AC: 33364 AN: 86256

European-Finnish (FIN) AF: 0.448 AC: 23921 AN: 53402

Middle Eastern (MID) AF: 0.369 AC: 2127 AN: 5768

European-Non Finnish (NFE) AF: 0.488 AC: 542554 AN: 1111866

Other (OTH) AF: 0.422 AC: 25477 AN: 60372

GnomAD4 genome AF: 0.350 AC: 53268 AN: 152024 Hom.: 11467 Cov.: 31 AF XY: 0.350 AC XY: 25995 AN XY: 74284

African (AFR) AF: 0.0917 AC: 3809 AN: 41520

American (AMR) AF: 0.393 AC: 6002 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1337 AN: 3464

East Asian (EAS) AF: 0.266 AC: 1368 AN: 5148

South Asian (SAS) AF: 0.386 AC: 1858 AN: 4812

European-Finnish (FIN) AF: 0.438 AC: 4625 AN: 10556

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.486 AC: 32987 AN: 67942

Other (OTH) AF: 0.362 AC: 765 AN: 2112

Alfa AF: 0.440 Hom.: 5003

Bravo AF: 0.335

TwinsUK AF: 0.490 AC: 1816

ALSPAC AF: 0.486 AC: 1872

ESP6500AA AF: 0.0983 AC: 407

ESP6500EA AF: 0.474 AC: 3979

ExAC AF: 0.414 AC: 50104

Asia WGS AF: 0.283 AC: 988 AN: 3478

EpiCase AF: 0.479

EpiControl AF: 0.474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Nemaline myopathy 2 (4)
-	-	2	not provided (2)
-	-	1	Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		3.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.026	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.55		Loss of ubiquitination at K2613 (P = 0.027)
MPC		0.37
ClinPred		0.085	T
GERP RS		5.8
Varity_R		0.46
gMVP		0.55
Mutation Taster		=99/1	polymorphism (auto)

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: rs13013209; hg19: chr2-152500449; COSMIC: COSV50813503;