rs34504204

chr2-151565084-T-Achr2-151565084-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001164507.2(NEB):c.18431A>T(p.His6144Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000076 in 1,447,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H6144R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.71

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11429396).
• BP6: Variant 2-151565084-T-A is Benign according to our data. Variant chr2-151565084-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 1378589.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.18431A>T	p.His6144Leu	missense_variant	117/182	ENST00000427231.7
NEB	NM_001164508.2	c.18431A>T	p.His6144Leu	missense_variant	117/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.18431A>T	p.His6144Leu	missense_variant	117/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.18431A>T	p.His6144Leu	missense_variant	117/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000244 AC: 6 AN: 246206 Hom.: 0 AF XY: 0.0000225 AC XY: 3 AN XY: 133554

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000448

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.00000760 AC: 11 AN: 1447142 Hom.: 0 Cov.: 28 AF XY: 0.00000555 AC XY: 4 AN XY: 720368

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000727

Gnomad4 OTH exome AF: 0.0000501

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	16
Dann	Benign	0.86
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.46	T;T;T;T;T;T;.;.
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.;.;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.4	N;N;.;D;N;D;.;.
REVEL	Benign	0.14
Sift	Benign	0.54	T;D;.;D;T;D;.;.
Sift4G	Benign	0.080	T;T;T;T;T;T;T;T
Polyphen		0.0030	.;.;.;.;B;.;.;.
Vest4		0.21
MutPred		0.49		Gain of stability (P = 0.0144);.;.;.;Gain of stability (P = 0.0144);.;.;.;
MVP		0.53
MPC		0.074
ClinPred		0.14	T
GERP RS		6.0
Varity_R		0.16
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs34504204; hg19: chr2-152421598;