2-151583609-T-C

Variant names:

• chr2-151583609-T-C
• rs45612241
• NM_001164507.2:c.15821A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001164508.2(NEB):​c.15821A>G​(p.Asn5274Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N5274I) has been classified as Likely benign. The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 5)
  • Exomes 𝑓: 0.0000026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08808878).

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.15821A>G	p.Asn5274Ser	missense	Exon 101 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.15821A>G	p.Asn5274Ser	missense	Exon 101 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.15821A>G	p.Asn5274Ser	missense	Exon 101 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.15821A>G	p.Asn5274Ser	missense	Exon 101 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.15821A>G	p.Asn5274Ser	missense	Exon 101 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000413693.5	TSL:5	c.11A>G	p.Asn4Ser	missense	Exon 1 of 74	ENSP00000410961.1	H0Y786

Frequencies

GnomAD3 genomes Cov.: 5

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000264 AC: 1 AN: 378372 Hom.: 0 Cov.: 2 AF XY: 0.00000503 AC XY: 1 AN XY: 198936

⚠️ 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: 11586

American (AMR) AF: 0.00 AC: 0 AN: 16462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12090

East Asian (EAS) AF: 0.0000440 AC: 1 AN: 22706

South Asian (SAS) AF: 0.00 AC: 0 AN: 39174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 228674

Other (OTH) AF: 0.00 AC: 0 AN: 22042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 5

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	16
DANN	Benign	0.67
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.1
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.078
Sift	Benign	1.0	T
Sift4G	Uncertain	0.014	D
Vest4		0.16
MutPred		0.35		Gain of disorder (P = 0.0447)
MVP		0.28
MPC		0.25
ClinPred		0.11	T
GERP RS		3.8
PromoterAI		-0.013	Neutral
gMVP		0.0021
Mutation Taster		=88/12	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: rs45612241; hg19: chr2-152440123;