rs78420579

chr2-151664541-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001164507.2(NEB):c.5411C>A(p.Ala1804Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000455 in 1,607,272 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1804T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (8 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 10.0

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011308938).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000276 (42/152308) while in subpopulation EAS AF= 0.0079 (41/5188). AF 95% confidence interval is 0.00599. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.5411C>A	p.Ala1804Glu	missense_variant	44/182	ENST00000427231.7
NEB	NM_001164508.2	c.5411C>A	p.Ala1804Glu	missense_variant	44/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.5411C>A	p.Ala1804Glu	missense_variant	44/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.5411C>A	p.Ala1804Glu	missense_variant	44/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.5411C>A	p.Ala1804Glu	missense_variant	44/150	5

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00788

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000838 AC: 20 AN: 238626 Hom.: 0 AF XY: 0.0000464 AC XY: 6 AN XY: 129182

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00116

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000474 AC: 690 AN: 1454964 Hom.: 8 Cov.: 30 AF XY: 0.000431 AC XY: 312 AN XY: 723080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0172

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00790

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000104 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.000108 AC: 13

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 23, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 21, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	22
Dann	Benign	0.54
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T;T;T;T;.;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.011	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N;N;.;N;N;N;N
MutationTaster	Benign	0.86	D;D;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N;N;.;N;N;.;.
REVEL	Benign	0.27
Sift	Uncertain	0.010	D;T;.;T;D;.;.
Sift4G	Uncertain	0.011	D;D;D;D;D;D;D
Polyphen		0.033	.;.;.;.;B;.;.
Vest4		0.17
MVP		0.47
MPC		0.061
ClinPred		0.19	T
GERP RS		6.1
Varity_R		0.30
gMVP		0.33

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: rs78420579; hg19: chr2-152521055; COSMIC: COSV51452037; COSMIC: COSV51452037;