2-151630818-C-T

Variant names:

• chr2-151630818-C-T
• rs111841612
• NM_001164507.2:c.9620G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001164508.2(NEB):​c.9620G>A​(p.Arg3207His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,587,284 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3207S) has been classified as Uncertain significance. The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: NEB NM_001164508.2 missense, splice_region
• Scores: Splicing: ADA: 0.01420
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 0.0740
• Publications: 4 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044703454).

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.9620G>A	p.Arg3207His	missense splice_region	Exon 67 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.9620G>A	p.Arg3207His	missense splice_region	Exon 67 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.9620G>A	p.Arg3207His	missense splice_region	Exon 67 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.9620G>A	p.Arg3207His	missense splice_region	Exon 67 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.9620G>A	p.Arg3207His	missense splice_region	Exon 67 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.8891G>A	p.Arg2964His	missense splice_region	Exon 64 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000202 AC: 45 AN: 223262 AF XY: 0.000266

Gnomad AFR exome AF: 0.000207

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000793

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.000205 AC: 294 AN: 1435162 Hom.: 1 Cov.: 29 AF XY: 0.000220 AC XY: 157 AN XY: 712270

African (AFR) AF: 0.000154 AC: 5 AN: 32524

American (AMR) AF: 0.0000249 AC: 1 AN: 40150

Ashkenazi Jewish (ASJ) AF: 0.000794 AC: 20 AN: 25182

East Asian (EAS) AF: 0.0000762 AC: 3 AN: 39366

South Asian (SAS) AF: 0.000390 AC: 32 AN: 81958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52888

Middle Eastern (MID) AF: 0.00300 AC: 17 AN: 5662

European-Non Finnish (NFE) AF: 0.000183 AC: 201 AN: 1098028

Other (OTH) AF: 0.000253 AC: 15 AN: 59404

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74356

African (AFR) AF: 0.000145 AC: 6 AN: 41486

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000185 Hom.: 0

Bravo AF: 0.000178

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.000191 AC: 23

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	2	-	Nemaline myopathy 2 (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Benign	0.11
Eigen_PC	Benign	-0.015
FATHMM_MKL	Benign	0.055	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.074
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.21
Sift	Benign	0.037	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.16
MVP		0.50
MPC		0.070
ClinPred		0.11	T
GERP RS		3.8
Varity_R		0.17
gMVP		0.16
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.11
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: rs111841612; hg19: chr2-152487332; COSMIC: COSV51086926;