rs543100735

chr2-151633716-T-Achr2-151633716-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_001164507.2(NEB):c.9352A>T(p.Thr3118Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000144 in 1,614,002 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). Synonymous variant affecting the same amino acid position (i.e. T3118T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 4.98

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30179924).
• BP6: Variant 2-151633716-T-A is Benign according to our data. Variant chr2-151633716-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257840.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.9352A>T	p.Thr3118Ser	missense_variant	65/182	ENST00000427231.7
NEB	NM_001164508.2	c.9352A>T	p.Thr3118Ser	missense_variant	65/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.9352A>T	p.Thr3118Ser	missense_variant	65/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.9352A>T	p.Thr3118Ser	missense_variant	65/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.8854-2538A>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152184 Hom.: 0 Cov.: 32

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000136 AC: 34 AN: 249112 Hom.: 0 AF XY: 0.000141 AC XY: 19 AN XY: 135132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

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: 0.000230

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000140 AC: 205 AN: 1461700 Hom.: 0 Cov.: 114 AF XY: 0.000144 AC XY: 105 AN XY: 727134

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

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: 0.000174

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74480

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000427 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

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

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 16, 2022	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 3118 of the NEB protein (p.Thr3118Ser). This variant is present in population databases (rs543100735, gnomAD 0.02%). 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: 257840). 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.	Jan 17, 2020	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 06, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	18
Dann	Benign	0.95
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T;T;.;.
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.30	T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	-1.4	N;.;N;.;.
REVEL	Benign	0.19
Sift	Benign	0.041	D;.;D;.;.
Sift4G	Uncertain	0.017	D;D;D;D;D
Vest4		0.51
MutPred		0.35		Gain of disorder (P = 0.1061);Gain of disorder (P = 0.1061);Gain of disorder (P = 0.1061);Gain of disorder (P = 0.1061);Gain of disorder (P = 0.1061);
MVP		0.56
MPC		0.22
ClinPred		0.11	T
GERP RS		5.9
gMVP		0.029

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: rs543100735; hg19: chr2-152490230;