2-151604563-G-T

Variant names:

• chr2-151604563-G-T
• rs1468240932
• NM_001164507.2:c.13056C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PP3_Strong BP6

The NM_001164508.2(NEB):​c.13056C>A​(p.Ser4352Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S4352S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000075 (0 hom., cov: 4)
  • Exomes 𝑓: 0.000033 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.0270
• 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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• BP6: Variant 2-151604563-G-T is Benign according to our data. Variant chr2-151604563-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 534044.

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.13056C>A	p.Ser4352Arg	missense	Exon 85 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.13056C>A	p.Ser4352Arg	missense	Exon 85 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.13056C>A	p.Ser4352Arg	missense	Exon 85 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.13056C>A	p.Ser4352Arg	missense	Exon 85 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.13056C>A	p.Ser4352Arg	missense	Exon 85 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.11601+5246C>A		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0000750 AC: 2 AN: 26650 Hom.: 0 Cov.: 4

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000119 AC: 5 AN: 42058 AF XY: 0.000185

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000770

Gnomad FIN 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: 0.0000328 AC: 10 AN: 304566 Hom.: 0 Cov.: 0 AF XY: 0.0000439 AC XY: 7 AN XY: 159392

⚠️ 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: 7712

American (AMR) AF: 0.00 AC: 0 AN: 13140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8982

East Asian (EAS) AF: 0.000491 AC: 10 AN: 20350

South Asian (SAS) AF: 0.00 AC: 0 AN: 31870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1266

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 185904

Other (OTH) AF: 0.00 AC: 0 AN: 17606

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000605286), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000751 AC: 2 AN: 26614 Hom.: 0 Cov.: 4 AF XY: 0.0000873 AC XY: 1 AN XY: 11452

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

African (AFR) AF: 0.00 AC: 0 AN: 4004

American (AMR) AF: 0.00 AC: 0 AN: 2654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 638

East Asian (EAS) AF: 0.00116 AC: 2 AN: 1720

South Asian (SAS) AF: 0.00 AC: 0 AN: 706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 146

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 14890

Other (OTH) AF: 0.00 AC: 0 AN: 370

⚠️ 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: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	6.9
DANN	Benign	0.58
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.23	D
PhyloP100		-0.027
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.61
MutPred		0.86		Gain of helix (P = 0.062)
MVP		0.67
MPC		0.30
ClinPred		0.20	T
GERP RS		1.3
gMVP		0.039
Mutation Taster		=66/34	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: rs1468240932; hg19: chr2-152461077;