chr2-151579498-T-A

Variant names:

• chr2-151579498-T-A
• rs62174690
• NM_001164507.2:c.16544A>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001164507.2(NEB):​c.16544A>T​(p.Lys5515Met) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K5515N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000081 (0 hom., cov: 17)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.29
• Publications: 4 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26775432).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.16544A>T	p.Lys5515Met	missense	Exon 105 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.16544A>T	p.Lys5515Met	missense	Exon 105 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.16544A>T	p.Lys5515Met	missense	Exon 105 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.16544A>T	p.Lys5515Met	missense	Exon 105 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.16544A>T	p.Lys5515Met	missense	Exon 105 of 182	ENSP00000416578.2
	NEB	ENST00000413693.5	TSL:5	c.734A>T	p.Lys245Met	missense	Exon 5 of 74	ENSP00000410961.1

Frequencies

GnomAD3 genomes AF: 0.00000807 AC: 1 AN: 123990 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000265

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.36e-7 AC: 1 AN: 1358928 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 671238

African (AFR) AF: 0.00 AC: 0 AN: 31456

American (AMR) AF: 0.00 AC: 0 AN: 35540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25118

East Asian (EAS) AF: 0.00 AC: 0 AN: 35596

South Asian (SAS) AF: 0.00 AC: 0 AN: 78852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4048

European-Non Finnish (NFE) AF: 9.59e-7 AC: 1 AN: 1042984

Other (OTH) AF: 0.00 AC: 0 AN: 56772

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000807 AC: 1 AN: 123990 Hom.: 0 Cov.: 17 AF XY: 0.0000170 AC XY: 1 AN XY: 58750

⚠️ 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: 36960

American (AMR) AF: 0.00 AC: 0 AN: 10640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3134

East Asian (EAS) AF: 0.00 AC: 0 AN: 4178

South Asian (SAS) AF: 0.000265 AC: 1 AN: 3772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 55624

Other (OTH) AF: 0.00 AC: 0 AN: 1592

⚠️ 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.: 281

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.049
Eigen_PC	Benign	-0.063
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.93	T
PhyloP100		2.3
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.14
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0090	D
Vest4		0.32
MutPred		0.58		Loss of methylation at K5515 (P = 0.0163)
MVP		0.45
MPC		0.35
ClinPred		0.69	D
GERP RS		3.6
gMVP		0.017
Mutation Taster		=91/9	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: rs62174690; hg19: chr2-152436012;