rs371689870

chr2-151562672-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_001164507.2(NEB):c.18830C>T(p.Thr6277Met) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,448,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T6277T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 3.82

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3781298).
• BP6: Variant 2-151562672-G-A is Benign according to our data. Variant chr2-151562672-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 576262.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.18830C>T	p.Thr6277Met	missense_variant	120/182	ENST00000427231.7
NEB	NM_001164508.2	c.18830C>T	p.Thr6277Met	missense_variant	120/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.18830C>T	p.Thr6277Met	missense_variant	120/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.18830C>T	p.Thr6277Met	missense_variant	120/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000245 AC: 6 AN: 245046 Hom.: 0 AF XY: 0.0000377 AC XY: 5 AN XY: 132718

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

Gnomad SAS exome AF: 0.0000336

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1448672 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 8 AN XY: 718444

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000353

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000817

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.000248 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Sep 08, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;T;D;T;T;T;.;.
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M;.;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.9	D;N;.;N;D;D;.;.
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D;D;.;D;D;D;.;.
Sift4G	Uncertain	0.029	D;D;D;D;D;T;D;D
Polyphen		0.99	.;.;.;.;D;.;.;.
Vest4		0.36
MVP		0.66
MPC		0.29
ClinPred		0.79	D
GERP RS		4.8
Varity_R		0.14
gMVP		0.44

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: rs371689870; hg19: chr2-152419186;