chr2-151569306-C-T

Variant names:

• chr2-151569306-C-T
• rs149881695
• NM_001164507.2:c.17497G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001164508.2(NEB):​c.17497G>A​(p.Val5833Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,613,846 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V5833A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (18 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 2.55
• Publications: 6 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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064363778).
• BP6: Variant 2-151569306-C-T is Benign according to our data. Variant chr2-151569306-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 252580.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00202 (308/152252) while in subpopulation SAS AF = 0.0056 (27/4822). AF 95% confidence interval is 0.00395. There are 0 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.17497G>A	p.Val5833Ile	missense	Exon 110 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.17497G>A	p.Val5833Ile	missense	Exon 110 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.17497G>A	p.Val5833Ile	missense	Exon 110 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.17497G>A	p.Val5833Ile	missense	Exon 110 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.17497G>A	p.Val5833Ile	missense	Exon 110 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.12394G>A	p.Val4132Ile	missense	Exon 83 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 305 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00265

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00221 AC: 550 AN: 249108 AF XY: 0.00252

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00237

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00290 AC: 4242 AN: 1461594 Hom.: 18 Cov.: 31 AF XY: 0.00305 AC XY: 2220 AN XY: 727096

African (AFR) AF: 0.000687 AC: 23 AN: 33478

American (AMR) AF: 0.00132 AC: 59 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 68 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00591 AC: 510 AN: 86258

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53400

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.00298 AC: 3312 AN: 1111782

Other (OTH) AF: 0.00381 AC: 230 AN: 60368

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74448

African (AFR) AF: 0.000626 AC: 26 AN: 41530

American (AMR) AF: 0.00347 AC: 53 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4822

European-Finnish (FIN) AF: 0.000849 AC: 9 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00266 AC: 181 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00242 Hom.: 4

Bravo AF: 0.00207

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000500 AC: 2

ESP6500EA AF: 0.00216 AC: 18

ExAC AF: 0.00228 AC: 276

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00273

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	Nemaline myopathy 2 (5)
-	1	3	not specified (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.10
Sift	Benign	0.064	T
Sift4G	Benign	0.15	T
Polyphen		0.54	P
Vest4		0.21
MVP		0.44
MPC		0.094
ClinPred		0.012	T
GERP RS		6.1
Varity_R		0.10
gMVP		0.56
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: rs149881695; hg19: chr2-152425820; COSMIC: COSV51466671;