chr2-151627640-C-G

Position:

• chr2-151627640-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_001164508.2(NEB):​c.10026G>C​(p.Lys3342Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000231 in 1,614,010 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.04

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=0.043038726).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00021 (32/152312) while in subpopulation EAS AF= 0.00348 (18/5178). AF 95% confidence interval is 0.00225. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. 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	Protein	UniProt
NEB	NM_001164507.2	c.10026G>C	p.Lys3342Asn	missense_variant	69/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.10026G>C	p.Lys3342Asn	missense_variant	69/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.10026G>C	p.Lys3342Asn	missense_variant	69/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.10026G>C	p.Lys3342Asn	missense_variant	69/182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.9297G>C	p.Lys3099Asn	missense_variant	66/150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000229 AC: 57 AN: 249222 Hom.: 0 AF XY: 0.000215 AC XY: 29 AN XY: 135194

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00139

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000233 AC: 341 AN: 1461698 Hom.: 1 Cov.: 32 AF XY: 0.000224 AC XY: 163 AN XY: 727134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00587

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00348

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.000238

ExAC AF: 0.000314 AC: 38

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2022	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 3342 of the NEB protein (p.Lys3342Asn). This variant is present in population databases (rs117636679, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 568797). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Oct 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;.;T;.;D;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;.;.
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.043	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.6	H;.;.;.;H;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.7	D;D;.;D;D;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.047	D;D;.;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.61
MutPred		0.54		Loss of ubiquitination at K3099 (P = 0.0412);.;.;.;Loss of ubiquitination at K3099 (P = 0.0412);.;.;
MVP		0.68
MPC		0.37
ClinPred		0.45	T
GERP RS		5.6
Varity_R		0.58
gMVP		0.68

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: rs117636679; hg19: chr2-152484154;