rs199907781

chr2-151729632-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001164507.2(NEB):c.61G>A(p.Glu21Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,613,162 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 2.46

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.61G>A	p.Glu21Lys	missense_variant	4/182	ENST00000427231.7
NEB	NM_001164508.2	c.61G>A	p.Glu21Lys	missense_variant	4/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.61G>A	p.Glu21Lys	missense_variant	4/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.61G>A	p.Glu21Lys	missense_variant	4/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.61G>A	p.Glu21Lys	missense_variant	4/150	5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000723 AC: 18 AN: 248870 Hom.: 0 AF XY: 0.0000444 AC XY: 6 AN XY: 135016

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: 0.000151

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000227 AC: 331 AN: 1461088 Hom.: 0 Cov.: 31 AF XY: 0.000194 AC XY: 141 AN XY: 726854

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

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: 0.000286

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74300

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000275 Hom.: 0

Bravo AF: 0.000185

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000744 AC: 9

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 13, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 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 -

Nemaline myopathy 2 Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Uncertain significance, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 15, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;.;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.32	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N;N;.;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.87	N;N;.;N;N;.;.
REVEL	Benign	0.059
Sift	Pathogenic	0.0	D;D;.;D;D;.;.
Sift4G	Uncertain	0.019	D;D;D;D;D;D;D
Polyphen		0.35	.;.;.;.;B;.;.
Vest4		0.63
MVP		0.40
MPC		0.056
ClinPred		0.31	T
GERP RS		4.7
Varity_R		0.23
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		Position offset: -17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199907781; hg19: chr2-152586146; COSMIC: COSV51469908;