rs201746137

chr2-151643271-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001164507.2(NEB):c.8039G>A(p.Arg2680Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,613,646 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.91

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16685367).
• BP6: Variant 2-151643271-C-T is Benign according to our data. Variant chr2-151643271-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465642.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.8039G>A	p.Arg2680Gln	missense_variant	58/182	ENST00000427231.7
NEB	NM_001164508.2	c.8039G>A	p.Arg2680Gln	missense_variant	58/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.8039G>A	p.Arg2680Gln	missense_variant	58/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.8039G>A	p.Arg2680Gln	missense_variant	58/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.8039G>A	p.Arg2680Gln	missense_variant	58/150	5

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152066 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000213 AC: 53 AN: 249092 Hom.: 1 AF XY: 0.000215 AC XY: 29 AN XY: 135118

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000381

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000146 AC: 213 AN: 1461580 Hom.: 1 Cov.: 31 AF XY: 0.000149 AC XY: 108 AN XY: 727062

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.000547

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152066 Hom.: 0 Cov.: 33 AF XY: 0.0000943 AC XY: 7 AN XY: 74252

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.000269 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000373 AC: 45

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.8039G>A (p.R2680Q) alteration is located in exon 58 (coding exon 56) of the NEB gene. This alteration results from a G to A substitution at nucleotide position 8039, causing the arginine (R) at amino acid position 2680 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;.;.
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	M;M;.;M;M;M;M
MutationTaster	Benign	0.90	D;D;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N;N;.;N;N;.;.
REVEL	Benign	0.11
Sift	Benign	0.12	T;D;.;D;T;.;.
Sift4G	Uncertain	0.011	D;D;D;D;D;D;D
Polyphen		0.97	.;.;.;.;D;.;.
Vest4		0.46
MVP		0.58
MPC		0.33
ClinPred		0.29	T
GERP RS		5.7
Varity_R		0.22
gMVP		0.26

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: rs201746137; hg19: chr2-152499785;