rs539139958

Variant names:

• chr2-151617468-G-A
• rs539139958
• NM_001164507.2:c.11077C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-151617468-G-A
• chr2-151617468-G-C
• chr2-151617468-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001164507.2(NEB):​c.11077C>T​(p.Arg3693Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,362,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3693H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000095 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: NEB NM_001164507.2 missense, splice_region
• Scores: Splicing: ADA: 0.9865
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.89
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. 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.11077C>T	p.Arg3693Cys	missense splice_region	Exon 75 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.11077C>T	p.Arg3693Cys	missense splice_region	Exon 75 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.11077C>T	p.Arg3693Cys	missense splice_region	Exon 75 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.11077C>T	p.Arg3693Cys	missense splice_region	Exon 75 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.11077C>T	p.Arg3693Cys	missense splice_region	Exon 75 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.10348C>T	p.Arg3450Cys	missense splice_region	Exon 72 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.0000948 AC: 13 AN: 137144 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000832

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000154

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000207 AC: 14 AN: 67566 AF XY: 0.000229

Gnomad AFR exome AF: 0.000205

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000273

Gnomad EAS exome AF: 0.000182

Gnomad FIN exome AF: 0.000507

Gnomad NFE exome AF: 0.000258

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000241 AC: 295 AN: 1225474 Hom.: 0 Cov.: 23 AF XY: 0.000224 AC XY: 135 AN XY: 601962

African (AFR) AF: 0.00 AC: 0 AN: 25650

American (AMR) AF: 0.00 AC: 0 AN: 22360

Ashkenazi Jewish (ASJ) AF: 0.000145 AC: 3 AN: 20754

East Asian (EAS) AF: 0.0000301 AC: 1 AN: 33170

South Asian (SAS) AF: 0.0000682 AC: 4 AN: 58634

European-Finnish (FIN) AF: 0.000120 AC: 4 AN: 33242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3830

European-Non Finnish (NFE) AF: 0.000285 AC: 278 AN: 976686

Other (OTH) AF: 0.0000978 AC: 5 AN: 51148

GnomAD4 genome AF: 0.0000948 AC: 13 AN: 137194 Hom.: 0 Cov.: 29 AF XY: 0.000106 AC XY: 7 AN XY: 65770

African (AFR) AF: 0.0000830 AC: 3 AN: 36138

American (AMR) AF: 0.00 AC: 0 AN: 13386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 4778

South Asian (SAS) AF: 0.00 AC: 0 AN: 4354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000154 AC: 10 AN: 64986

Other (OTH) AF: 0.00 AC: 0 AN: 1882

Alfa AF: 0.000180 Hom.: 0

ExAC AF: 0.0000575 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		1.9
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.37
Sift	Benign	0.052	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.37
MVP		0.67
MPC		0.37
ClinPred		0.29	T
GERP RS		5.2
Varity_R		0.13
gMVP		0.36
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.84
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: rs539139958; hg19: chr2-152473982;