rs533898172

chr2-151633935-G-Achr2-151633935-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001164507.2(NEB):c.9133C>T(p.Leu3045Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,613,670 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict 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. L3045L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.02

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0234631).
• BP6: Variant 2-151633935-G-A is Benign according to our data. Variant chr2-151633935-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 465649.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151633935-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.9133C>T	p.Leu3045Phe	missense_variant	65/182	ENST00000427231.7
NEB	NM_001164508.2	c.9133C>T	p.Leu3045Phe	missense_variant	65/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.9133C>T	p.Leu3045Phe	missense_variant	65/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.9133C>T	p.Leu3045Phe	missense_variant	65/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.8854-2757C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000325 AC: 81 AN: 249064 Hom.: 1 AF XY: 0.000444 AC XY: 60 AN XY: 135098

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000114 AC: 166 AN: 1461354 Hom.: 1 Cov.: 113 AF XY: 0.000165 AC XY: 120 AN XY: 726910

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74472

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.000315 AC: 38

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 27, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.91	D;D;D;.;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.023	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	-1.4	N;.;N;.;.
REVEL	Benign	0.14
Sift	Benign	0.033	D;.;D;.;.
Sift4G	Uncertain	0.051	T;T;T;T;T
Vest4		0.58
MutPred		0.49		Loss of ubiquitination at K3043 (P = 0.1083);Loss of ubiquitination at K3043 (P = 0.1083);Loss of ubiquitination at K3043 (P = 0.1083);Loss of ubiquitination at K3043 (P = 0.1083);Loss of ubiquitination at K3043 (P = 0.1083);
MVP		0.30
MPC		0.27
ClinPred		0.094	T
GERP RS		4.2
gMVP		0.011

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: rs533898172; hg19: chr2-152490449; COSMIC: COSV51423574;