rs886038435

Variant names:

• chr2-151600696-C-T
• rs886038435
• NM_001164507.2:c.13534G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001164508.2(NEB):​c.13534G>A​(p.Ala4512Thr) 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). Synonymous variant affecting the same amino acid position (i.e. A4512A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.058 (0 hom., cov: 0)
  • Exomes 𝑓: 0.032 (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:3
• Conservation: PhyloP100: -5.64
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038007498).
• BP6: Variant 2-151600696-C-T is Benign according to our data. Variant chr2-151600696-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257734.

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.13534G>A	p.Ala4512Thr	missense	Exon 89 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.13534G>A	p.Ala4512Thr	missense	Exon 89 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.13534G>A	p.Ala4512Thr	missense	Exon 89 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.13534G>A	p.Ala4512Thr	missense	Exon 89 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.13534G>A	p.Ala4512Thr	missense	Exon 89 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.11601+9113G>A		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0577 AC: 9 AN: 156 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0556

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: 0.0921

Gnomad OTH AF: 0.250

GnomAD2 exomes AF: 0.0240 AC: 308 AN: 12824 AF XY: 0.0245

Gnomad AFR exome AF: 0.0245

Gnomad AMR exome AF: 0.0166

Gnomad ASJ exome AF: 0.0342

Gnomad EAS exome AF: 0.0108

Gnomad FIN exome AF: 0.0481

Gnomad NFE exome AF: 0.0345

Gnomad OTH exome AF: 0.0249

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0324 AC: 756 AN: 23342 Hom.: 0 Cov.: 0 AF XY: 0.0333 AC XY: 431 AN XY: 12940

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

African (AFR) AF: 0.0252 AC: 8 AN: 318

American (AMR) AF: 0.0141 AC: 37 AN: 2626

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 14 AN: 302

East Asian (EAS) AF: 0.0182 AC: 19 AN: 1042

South Asian (SAS) AF: 0.0295 AC: 126 AN: 4266

European-Finnish (FIN) AF: 0.0554 AC: 36 AN: 650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 32

European-Non Finnish (NFE) AF: 0.0364 AC: 479 AN: 13160

Other (OTH) AF: 0.0391 AC: 37 AN: 946

⚠️ 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 AF: 0.0584 AC: 9 AN: 154 Hom.: 0 Cov.: 0 AF XY: 0.0610 AC XY: 5 AN XY: 82

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

African (AFR) AF: 0.0556 AC: 1 AN: 18

American (AMR) AF: 0.00 AC: 0 AN: 28

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 16

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0921 AC: 7 AN: 76

Other (OTH) AF: 0.250 AC: 1 AN: 4

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000000222045), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0141 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.50
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.010	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.97	T
PhyloP100		-5.6
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.014
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.024	D
Vest4		0.21
MutPred		0.39		Gain of phosphorylation at A4512 (P = 0.053)
MPC		0.22
ClinPred		0.010	T
GERP RS		0.54
gMVP		0.00074
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886038435; hg19: chr2-152457210;