2-151581575-C-T

Variant names:

• chr2-151581575-C-T
• rs750810441
• NM_001164507.2:c.16192G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164508.2(NEB):​c.16192G>A​(p.Asp5398Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D5398H) has been classified as Uncertain significance. The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 19)
  • Exomes 𝑓: 0.0020 (18 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.35
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007758349).
• BP6: Variant 2-151581575-C-T is Benign according to our data. Variant chr2-151581575-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 257757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00208 (283/136330) while in subpopulation AMR AF = 0.00418 (55/13154). AF 95% confidence interval is 0.0033. There are 1 homozygotes in GnomAd4. There are 144 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 AD,AR gene

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.16192G>A	p.Asp5398Asn	missense	Exon 103 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.16192G>A	p.Asp5398Asn	missense	Exon 103 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.16192G>A	p.Asp5398Asn	missense	Exon 103 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.16192G>A	p.Asp5398Asn	missense	Exon 103 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.16192G>A	p.Asp5398Asn	missense	Exon 103 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000413693.5	TSL:5	c.382G>A	p.Asp128Asn	missense	Exon 3 of 74	ENSP00000410961.1	H0Y786

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 281 AN: 136244 Hom.: 1 Cov.: 19

Gnomad AFR AF: 0.000753

Gnomad AMI AF: 0.0102

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.00151

Gnomad FIN AF: 0.000822

Gnomad MID AF: 0.00671

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.00391

GnomAD2 exomes AF: 0.00219 AC: 215 AN: 98020 AF XY: 0.00236

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00288

Gnomad ASJ exome AF: 0.00763

Gnomad EAS exome AF: 0.00177

Gnomad FIN exome AF: 0.000883

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00331

GnomAD4 exome AF: 0.00196 AC: 1422 AN: 725896 Hom.: 18 Cov.: 10 AF XY: 0.00206 AC XY: 780 AN XY: 379416

African (AFR) AF: 0.00107 AC: 18 AN: 16900

American (AMR) AF: 0.00294 AC: 68 AN: 23140

Ashkenazi Jewish (ASJ) AF: 0.00999 AC: 183 AN: 18310

East Asian (EAS) AF: 0.00199 AC: 64 AN: 32124

South Asian (SAS) AF: 0.00413 AC: 241 AN: 58330

European-Finnish (FIN) AF: 0.000503 AC: 24 AN: 47752

Middle Eastern (MID) AF: 0.00948 AC: 25 AN: 2636

European-Non Finnish (NFE) AF: 0.00134 AC: 660 AN: 491578

Other (OTH) AF: 0.00396 AC: 139 AN: 35126

GnomAD4 genome AF: 0.00208 AC: 283 AN: 136330 Hom.: 1 Cov.: 19 AF XY: 0.00220 AC XY: 144 AN XY: 65390

African (AFR) AF: 0.000807 AC: 29 AN: 35946

American (AMR) AF: 0.00418 AC: 55 AN: 13154

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 38 AN: 3304

East Asian (EAS) AF: 0.00387 AC: 17 AN: 4388

South Asian (SAS) AF: 0.00151 AC: 6 AN: 3980

European-Finnish (FIN) AF: 0.000822 AC: 7 AN: 8518

Middle Eastern (MID) AF: 0.00714 AC: 2 AN: 280

European-Non Finnish (NFE) AF: 0.00176 AC: 113 AN: 64070

Other (OTH) AF: 0.00388 AC: 7 AN: 1806

Alfa AF: 0.00159 Hom.: 2

ExAC AF: 0.00294 AC: 62

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0057	T
Eigen	Benign	0.00043
Eigen_PC	Benign	0.056
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.99	T
PhyloP100		2.3
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.071
Sift	Benign	0.068	T
Sift4G	Uncertain	0.022	D
Vest4		0.23
MVP		0.58
MPC		0.28
ClinPred		0.013	T
GERP RS		4.3
gMVP		0.0065
Mutation Taster		=99/1	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: rs750810441; hg19: chr2-152438089;