2-151604811-G-T

Variant names:

• chr2-151604811-G-T
• rs1057524648
• NM_001164507.2:c.12808C>A

Variant summary

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

The NM_001164508.2(NEB):​c.12808C>A​(p.Gln4270Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 7)
  • Exomes 𝑓: 0.000017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.60
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11250013).
• BP6: Variant 2-151604811-G-T is Benign according to our data. Variant chr2-151604811-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 392823.

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.12808C>A	p.Gln4270Lys	missense	Exon 85 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.12808C>A	p.Gln4270Lys	missense	Exon 85 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.12808C>A	p.Gln4270Lys	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.12808C>A	p.Gln4270Lys	missense	Exon 85 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.12808C>A	p.Gln4270Lys	missense	Exon 85 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.11601+4998C>A		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes Cov.: 7

GnomAD2 exomes AF: 0.0000191 AC: 1 AN: 52294 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000482

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000173 AC: 8 AN: 462928 Hom.: 0 Cov.: 5 AF XY: 0.0000246 AC XY: 6 AN XY: 243476

⚠️ 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: 11200

American (AMR) AF: 0.00 AC: 0 AN: 18436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12980

East Asian (EAS) AF: 0.00 AC: 0 AN: 25130

South Asian (SAS) AF: 0.00 AC: 0 AN: 44288

European-Finnish (FIN) AF: 0.0000395 AC: 1 AN: 25348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1814

European-Non Finnish (NFE) AF: 0.0000234 AC: 7 AN: 299038

Other (OTH) AF: 0.00 AC: 0 AN: 24694

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 7

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	3.3
DANN	Benign	0.43
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.99	T
PhyloP100		-3.6
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.038
Sift	Benign	0.61	T
Sift4G	Benign	0.092	T
Vest4		0.19
MutPred		0.49		Gain of ubiquitination at Q4270 (P = 0.0238)
MVP		0.20
MPC		0.14
ClinPred		0.022	T
GERP RS		1.0
gMVP		0.00074
Mutation Taster		=89/11	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: rs1057524648; hg19: chr2-152461325;