rs143933602

chr2-151636258-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_001164507.2(NEB):c.9071C>T(p.Ala3024Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,610,070 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A3024A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (5 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 9.52

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07748878).
• BP6: Variant 2-151636258-G-A is Benign according to our data. Variant chr2-151636258-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257836.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4}. Variant chr2-151636258-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00235 (3432/1457708) while in subpopulation NFE AF= 0.00295 (3275/1111654). AF 95% confidence interval is 0.00286. There are 5 homozygotes in gnomad4_exome. There are 1637 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.9071C>T	p.Ala3024Val	missense_variant	64/182	ENST00000427231.7
NEB	NM_001164508.2	c.9071C>T	p.Ala3024Val	missense_variant	64/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.9071C>T	p.Ala3024Val	missense_variant	64/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.9071C>T	p.Ala3024Val	missense_variant	64/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.8853+3635C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152244 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00220

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00119 AC: 294 AN: 246034 Hom.: 0 AF XY: 0.00123 AC XY: 164 AN XY: 133704

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000159

Gnomad NFE exome AF: 0.00221

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00235 AC: 3432 AN: 1457708 Hom.: 5 Cov.: 31 AF XY: 0.00226 AC XY: 1637 AN XY: 725252

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000161

Gnomad4 NFE exome AF: 0.00295

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.00156 AC: 238 AN: 152362 Hom.: 1 Cov.: 32 AF XY: 0.00156 AC XY: 116 AN XY: 74510

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00220

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00243 Hom.: 5

Bravo AF: 0.00171

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00578 AC: 8

ESP6500EA AF: 0.00440 AC: 14

ExAC AF: 0.00107 AC: 129

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 05, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	NEB: BP4 -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 09, 2022	Variant summary: NEB c.9071C>T (p.Ala3024Val) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 246034 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NEB causing Nemaline Myopathy 2 (0.0012 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.9071C>T in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 2 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;.;.
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.077	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-1.9	N;.;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.11	T;.;T;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D
Vest4		0.68
MVP		0.44
MPC		0.32
ClinPred		0.061	T
GERP RS		6.0
gMVP		0.059

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: rs143933602; hg19: chr2-152492772; COSMIC: COSV99427149;