rs201971223

chr2-151565051-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001164507.2(NEB):c.18464A>C(p.Tyr6155Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000262 in 1,558,308 control chromosomes in the GnomAD database, including 3 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. Y6155Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (2 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.72

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014196157).
• BP6: Variant 2-151565051-T-G is Benign according to our data. Variant chr2-151565051-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 385695.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00144 (220/152344) while in subpopulation AFR AF= 0.00517 (215/41582). AF 95% confidence interval is 0.0046. There are 1 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.18464A>C	p.Tyr6155Ser	missense_variant	117/182	ENST00000427231.7
NEB	NM_001164508.2	c.18464A>C	p.Tyr6155Ser	missense_variant	117/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.18464A>C	p.Tyr6155Ser	missense_variant	117/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.18464A>C	p.Tyr6155Ser	missense_variant	117/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152226 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00514

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000387 AC: 93 AN: 240502 Hom.: 1 AF XY: 0.000246 AC XY: 32 AN XY: 130140

Gnomad AFR exome AF: 0.00588

Gnomad AMR exome AF: 0.0000895

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: 0.00

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.000134 AC: 189 AN: 1405964 Hom.: 2 Cov.: 27 AF XY: 0.000120 AC XY: 84 AN XY: 701476

Gnomad4 AFR exome AF: 0.00546

Gnomad4 AMR exome AF: 0.0000456

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: 0.00

Gnomad4 OTH exome AF: 0.000188

GnomAD4 genome AF: 0.00144 AC: 220 AN: 152344 Hom.: 1 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74502

Gnomad4 AFR AF: 0.00517

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000314 Hom.: 0

Bravo AF: 0.00162

ESP6500AA AF: 0.00575 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000456 AC: 55

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 11, 2018	- -

Nemaline myopathy 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2024

The c.13361A>C (p.Y4454S) alteration is located in exon 90 (coding exon 88) of the NEB gene. This alteration results from a A to C substitution at nucleotide position 13361, causing the tyrosine (Y) at amino acid position 4454 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 12, 2017

- -

NEB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	21
Dann	Benign	0.96
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;.;.
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.014	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.4	M;.;.;.;M;.;.;.
MutationTaster	Benign	0.51	N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.5	N;D;.;D;N;D;.;.
REVEL	Benign	0.27
Sift	Uncertain	0.016	D;T;.;T;D;D;.;.
Sift4G	Uncertain	0.016	D;D;D;D;D;T;D;D
Polyphen		0.035	.;.;.;.;B;.;.;.
Vest4		0.58
MVP		0.57
MPC		0.21
ClinPred		0.041	T
GERP RS		6.0
Varity_R		0.18
gMVP		0.52

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: rs201971223; hg19: chr2-152421565;