rs1462818722

Variant names:

• chr2-151604601-C-T
• rs1462818722
• NM_001164507.2:c.13018G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001164508.2(NEB):​c.13018G>A​(p.Asp4340Asn) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D4340D) has been classified as Likely benign. The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 4)
  • Exomes 𝑓: 0.000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.88
• 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: 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40437916).

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.13018G>A	p.Asp4340Asn	missense	Exon 85 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.13018G>A	p.Asp4340Asn	missense	Exon 85 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.13018G>A	p.Asp4340Asn	missense	Exon 85 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.13018G>A	p.Asp4340Asn	missense	Exon 85 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.13018G>A	p.Asp4340Asn	missense	Exon 85 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.11601+5208G>A		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 19314 Hom.: 0 Cov.: 4

Gnomad AFR AF: 0.00

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: 0.0000213 AC: 1 AN: 47032 AF XY: 0.0000417

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000274 AC: 10 AN: 365338 Hom.: 0 Cov.: 0 AF XY: 0.0000261 AC XY: 5 AN XY: 191280

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

African (AFR) AF: 0.00 AC: 0 AN: 9184

American (AMR) AF: 0.00 AC: 0 AN: 15520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11092

East Asian (EAS) AF: 0.00 AC: 0 AN: 24846

South Asian (SAS) AF: 0.0000270 AC: 1 AN: 36988

European-Finnish (FIN) AF: 0.0000448 AC: 1 AN: 22304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1552

European-Non Finnish (NFE) AF: 0.0000359 AC: 8 AN: 222754

Other (OTH) AF: 0.00 AC: 0 AN: 21098

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000010504), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 19314 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 8116

African (AFR) AF: 0.00 AC: 0 AN: 2676

American (AMR) AF: 0.00 AC: 0 AN: 1932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 472

East Asian (EAS) AF: 0.00 AC: 0 AN: 1450

South Asian (SAS) AF: 0.00 AC: 0 AN: 642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 130

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 11118

Other (OTH) AF: 0.00 AC: 0 AN: 290

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Nemaline myopathy 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.024	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.098
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.84	T
PhyloP100		4.9
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.13
Sift	Benign	0.10	T
Sift4G	Pathogenic	0.0	D
Vest4		0.43
MutPred		0.46		Loss of ubiquitination at K4345 (P = 0.1083)
MVP		0.68
MPC		0.31
ClinPred		0.26	T
GERP RS		3.2
gMVP		0.0062
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: rs1462818722; hg19: chr2-152461115;