rs200637566

chr2-151678000-G-Achr2-151678000-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001164507.2(NEB):c.3443C>T(p.Ala1148Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,613,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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. A1148E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.989

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04457292).
• BP6: Variant 2-151678000-G-A is Benign according to our data. Variant chr2-151678000-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 331519.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=1}. Variant chr2-151678000-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.3443C>T	p.Ala1148Val	missense_variant	33/182	ENST00000427231.7
NEB	NM_001164508.2	c.3443C>T	p.Ala1148Val	missense_variant	33/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.3443C>T	p.Ala1148Val	missense_variant	33/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.3443C>T	p.Ala1148Val	missense_variant	33/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.3443C>T	p.Ala1148Val	missense_variant	33/150	5

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000265 AC: 66 AN: 249056 Hom.: 0 AF XY: 0.000281 AC XY: 38 AN XY: 135112

Gnomad AFR exome AF: 0.000646

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00195

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.0000797

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000123 AC: 180 AN: 1461658 Hom.: 0 Cov.: 31 AF XY: 0.000116 AC XY: 84 AN XY: 727112

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00134

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74426

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.000314

ESP6500AA AF: 0.000251 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000289 AC: 35

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

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 12, 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.	Jan 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 29, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.029
Eigen_PC	Benign	0.0054
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.95	D;D;D;D;D;.;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.045	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;M;.;M;M;M;M
MutationTaster	Benign	0.81	D;D;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.7	N;N;.;N;N;.;.
REVEL	Benign	0.048
Sift	Benign	0.48	T;T;.;T;T;.;.
Sift4G	Benign	0.13	T;T;T;T;T;T;T
Polyphen		0.66	.;.;.;.;P;.;.
Vest4		0.63
MVP		0.48
MPC		0.25
ClinPred		0.023	T
GERP RS		4.3
Varity_R		0.071
gMVP		0.36

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: rs200637566; hg19: chr2-152534514;