rs78733601

Variant names:

• chr2-151655360-A-C
• rs78733601
• NM_001164507.2:c.6717T>G

Variant summary

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

The NM_001271208.2(NEB):​c.6717T>G​(p.Ile2239Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 1,581,574 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (80 hom.)
• Consequence: NEB NM_001271208.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.03
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022902489).
• BP6: Variant 2-151655360-A-C is Benign according to our data. Variant chr2-151655360-A-C is described in ClinVar as Benign. ClinVar VariationId is 129755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0577 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271208.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.6717T>G	p.Ile2239Met	missense	Exon 51 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.6717T>G	p.Ile2239Met	missense	Exon 51 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.6717T>G	p.Ile2239Met	missense	Exon 51 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.6717T>G	p.Ile2239Met	missense	Exon 51 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.6717T>G	p.Ile2239Met	missense	Exon 51 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.6717T>G	p.Ile2239Met	missense	Exon 51 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1678 AN: 152022 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00289

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0632

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00752 AC: 1818 AN: 241768 AF XY: 0.00650

Gnomad AFR exome AF: 0.0316

Gnomad AMR exome AF: 0.00190

Gnomad ASJ exome AF: 0.000405

Gnomad EAS exome AF: 0.0649

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000389

Gnomad OTH exome AF: 0.00581

GnomAD4 exome AF: 0.00293 AC: 4194 AN: 1429434 Hom.: 80 Cov.: 26 AF XY: 0.00287 AC XY: 2042 AN XY: 711646

African (AFR) AF: 0.0336 AC: 1101 AN: 32726

American (AMR) AF: 0.00182 AC: 79 AN: 43524

Ashkenazi Jewish (ASJ) AF: 0.000272 AC: 7 AN: 25724

East Asian (EAS) AF: 0.0541 AC: 2120 AN: 39200

South Asian (SAS) AF: 0.00224 AC: 184 AN: 82064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51854

Middle Eastern (MID) AF: 0.00511 AC: 29 AN: 5678

European-Non Finnish (NFE) AF: 0.000252 AC: 275 AN: 1089500

Other (OTH) AF: 0.00674 AC: 399 AN: 59164

GnomAD4 genome AF: 0.0111 AC: 1683 AN: 152140 Hom.: 36 Cov.: 32 AF XY: 0.0112 AC XY: 833 AN XY: 74382

African (AFR) AF: 0.0301 AC: 1249 AN: 41506

American (AMR) AF: 0.00282 AC: 43 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.0633 AC: 327 AN: 5162

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4820

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68008

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.00603 Hom.: 78

Bravo AF: 0.0127

ESP6500AA AF: 0.0270 AC: 98

ESP6500EA AF: 0.000367 AC: 3

ExAC AF: 0.00766 AC: 924

Asia WGS AF: 0.0470 AC: 162 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Nemaline myopathy 2 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.075
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.0
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.061
Sift	Benign	0.13	T
Sift4G	Uncertain	0.057	T
Polyphen		0.085	B
Vest4		0.22
MVP		0.44
MPC		0.19
ClinPred		0.031	T
GERP RS		3.5
Varity_R		0.060
gMVP		0.11
Mutation Taster		=100/0	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: rs78733601; hg19: chr2-152511874; COSMIC: COSV50812550;