rs886038442

Variant names:

• chr2-151593104-C-T
• rs886038442
• NM_001164507.2:c.14633G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4 BP6_Moderate

The NM_001164508.2(NEB):​c.14633G>A​(p.Arg4878His) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.86
• Publications: 2 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27297032).
• BP6: Variant 2-151593104-C-T is Benign according to our data. Variant chr2-151593104-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 257742.Status of the report is criteria_provided_single_submitter, 1 stars.

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.14633G>A	p.Arg4878His	missense	Exon 94 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.14633G>A	p.Arg4878His	missense	Exon 94 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.14633G>A	p.Arg4878His	missense	Exon 94 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.14633G>A	p.Arg4878His	missense	Exon 94 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.14633G>A	p.Arg4878His	missense	Exon 94 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.11601+16705G>A		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 66 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMR AF: 0.00

Gnomad SAS AF: 0.00

Gnomad NFE AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 176 AF XY: 0.00

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 NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000168 AC: 19 AN: 113280 Hom.: 0 Cov.: 0 AF XY: 0.000182 AC XY: 11 AN XY: 60456

⚠️ 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: 4056

American (AMR) AF: 0.000146 AC: 1 AN: 6848

Ashkenazi Jewish (ASJ) AF: 0.000287 AC: 1 AN: 3480

East Asian (EAS) AF: 0.00 AC: 0 AN: 4612

South Asian (SAS) AF: 0.00 AC: 0 AN: 17686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 458

European-Non Finnish (NFE) AF: 0.000258 AC: 17 AN: 65804

Other (OTH) AF: 0.00 AC: 0 AN: 6088

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000169231), 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: 66 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 40

African (AFR) AF: 0.00 AC: 0 AN: 38

American (AMR) AF: 0.00 AC: 0 AN: 6

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 18

Other (OTH) AC: 0 AN: 0

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	23
DANN	Benign	0.89
DEOGEN2	Benign	0.021	T
Eigen	Benign	0.084
Eigen_PC	Benign	-0.025
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.0	T
PhyloP100		5.9
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.15
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Vest4		0.41
MutPred		0.51		Loss of MoRF binding (P = 0.0123)
MVP		0.51
MPC		0.37
ClinPred		0.32	T
GERP RS		2.6
gMVP		0.014
Mutation Taster		=73/27	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: rs886038442; hg19: chr2-152449618;