2-151607547-G-A

Variant names:

• chr2-151607547-G-A
• rs1365594299
• NM_001164507.2:c.12596C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001164507.2(NEB):​c.12596C>T​(p.Pro4199Leu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P4199P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000012 (0 hom., cov: 11)
  • Exomes 𝑓: 0.000013 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.40
• 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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

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.12596C>T	p.Pro4199Leu	missense	Exon 83 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.12596C>T	p.Pro4199Leu	missense	Exon 83 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.12596C>T	p.Pro4199Leu	missense	Exon 83 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.12596C>T	p.Pro4199Leu	missense	Exon 83 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.12596C>T	p.Pro4199Leu	missense	Exon 83 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.11601+2262C>T		intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.0000123 AC: 1 AN: 81406 Hom.: 0 Cov.: 11

Gnomad AFR AF: 0.0000298

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000477 AC: 4 AN: 83828 AF XY: 0.00

Gnomad AFR exome AF: 0.000273

Gnomad AMR exome AF: 0.000200

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000128 AC: 8 AN: 623588 Hom.: 3 Cov.: 7 AF XY: 0.00000624 AC XY: 2 AN XY: 320434

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000727 AC: 2 AN: 27494

American (AMR) AF: 0.000116 AC: 2 AN: 17174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17814

East Asian (EAS) AF: 0.00 AC: 0 AN: 19506

South Asian (SAS) AF: 0.00 AC: 0 AN: 58278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2288

European-Non Finnish (NFE) AF: 0.00000928 AC: 4 AN: 430820

Other (OTH) AF: 0.00 AC: 0 AN: 29930

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000123 AC: 1 AN: 81406 Hom.: 0 Cov.: 11 AF XY: 0.0000261 AC XY: 1 AN XY: 38372

African (AFR) AF: 0.0000298 AC: 1 AN: 33570

American (AMR) AF: 0.00 AC: 0 AN: 5212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2218

East Asian (EAS) AF: 0.00 AC: 0 AN: 2174

South Asian (SAS) AF: 0.00 AC: 0 AN: 2370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 164

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 30392

Other (OTH) AF: 0.00 AC: 0 AN: 1002

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2

Nov 11, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 20, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Benign	0.63
DEOGEN2	Benign	0.051	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.39	D
PhyloP100		4.4
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.020	D
Sift4G	Pathogenic	0.0	D
Vest4		0.55
MutPred		0.83		Loss of disorder (P = 0.0446)
MVP		0.79
MPC		0.33
ClinPred		0.091	T
GERP RS		3.7
gMVP		0.0068
Mutation Taster		=76/24	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: rs1365594299; hg19: chr2-152464061;