2-151602679-C-T

Variant names:

• chr2-151602679-C-T
• rs876657540
• NM_001164507.2:c.13276G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001271208.2(NEB):​c.13276G>A​(p.Asp4426Asn) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000089 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001271208.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 1.70
• 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: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21040237).
• BP6: Variant 2-151602679-C-T is Benign according to our data. Variant chr2-151602679-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227726.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271208.2. 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.13276G>A	p.Asp4426Asn	missense	Exon 87 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.13276G>A	p.Asp4426Asn	missense	Exon 87 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.13276G>A	p.Asp4426Asn	missense	Exon 87 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.13276G>A	p.Asp4426Asn	missense	Exon 87 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.13276G>A	p.Asp4426Asn	missense	Exon 87 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.11601+7130G>A		intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 2 AN: 5074 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000249

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000889 AC: 6 AN: 67488 Hom.: 1 Cov.: 0 AF XY: 0.0000840 AC XY: 3 AN XY: 35698

African (AFR) AF: 0.00806 AC: 1 AN: 124

American (AMR) AF: 0.000489 AC: 1 AN: 2044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 884

East Asian (EAS) AF: 0.000956 AC: 1 AN: 1046

South Asian (SAS) AF: 0.000494 AC: 2 AN: 4048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 152

European-Non Finnish (NFE) AF: 0.0000214 AC: 1 AN: 46822

Other (OTH) AF: 0.00 AC: 0 AN: 2104

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000394 AC: 2 AN: 5076 Hom.: 0 Cov.: 0 AF XY: 0.000432 AC XY: 1 AN XY: 2314

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00581 AC: 1 AN: 172

American (AMR) AF: 0.00 AC: 0 AN: 312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 100

East Asian (EAS) AF: 0.00 AC: 0 AN: 104

South Asian (SAS) AF: 0.00 AC: 0 AN: 36

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.000249 AC: 1 AN: 4016

Other (OTH) AF: 0.00 AC: 0 AN: 62

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000769 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Uncertain	24
DANN	Benign	0.82
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.7
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.040
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.010	D
Vest4		0.16
MutPred		0.33		Loss of phosphorylation at Y4424 (P = 0.1443)
MVP		0.56
MPC		0.31
ClinPred		0.21	T
GERP RS		3.5
gMVP		0.0081
Mutation Taster		=93/7	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: rs876657540; hg19: chr2-152459193;