2-151581575-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001164507.2(NEB):c.16192G>A(p.Asp5398Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D5398H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 19)
  • Exomes 𝑓: 0.0020 (18 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.35

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007758349).
• BP6: Variant 2-151581575-C-T is Benign according to our data. Variant chr2-151581575-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151581575-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00208 (283/136330) while in subpopulation AMR AF= 0.00418 (55/13154). AF 95% confidence interval is 0.0033. There are 1 homozygotes in gnomad4. There are 144 alleles in male gnomad4 subpopulation. Median coverage is 19. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.16192G>A	p.Asp5398Asn	missense_variant	103/182	ENST00000427231.7
NEB	NM_001164508.2	c.16192G>A	p.Asp5398Asn	missense_variant	103/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.16192G>A	p.Asp5398Asn	missense_variant	103/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.16192G>A	p.Asp5398Asn	missense_variant	103/182	5	NM_001164507.2	A2
NEB	ENST00000413693.5	c.382G>A	p.Asp128Asn	missense_variant	3/74	5
NEB	ENST00000409198.5	c.11602-5221G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 281 AN: 136244 Hom.: 1 Cov.: 19

Gnomad AFR AF: 0.000753

Gnomad AMI AF: 0.0102

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.00151

Gnomad FIN AF: 0.000822

Gnomad MID AF: 0.00671

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.00391

GnomAD3 exomes AF: 0.00219 AC: 215 AN: 98020 Hom.: 1 AF XY: 0.00236 AC XY: 121 AN XY: 51206

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00288

Gnomad ASJ exome AF: 0.00763

Gnomad EAS exome AF: 0.00177

Gnomad SAS exome AF: 0.00409

Gnomad FIN exome AF: 0.000883

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00331

GnomAD4 exome AF: 0.00196 AC: 1422 AN: 725896 Hom.: 18 Cov.: 10 AF XY: 0.00206 AC XY: 780 AN XY: 379416

Gnomad4 AFR exome AF: 0.00107

Gnomad4 AMR exome AF: 0.00294

Gnomad4 ASJ exome AF: 0.00999

Gnomad4 EAS exome AF: 0.00199

Gnomad4 SAS exome AF: 0.00413

Gnomad4 FIN exome AF: 0.000503

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.00396

GnomAD4 genome AF: 0.00208 AC: 283 AN: 136330 Hom.: 1 Cov.: 19 AF XY: 0.00220 AC XY: 144 AN XY: 65390

Gnomad4 AFR AF: 0.000807

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00387

Gnomad4 SAS AF: 0.00151

Gnomad4 FIN AF: 0.000822

Gnomad4 NFE AF: 0.00176

Gnomad4 OTH AF: 0.00388

Alfa AF: 0.00159 Hom.: 2

ExAC AF: 0.00294 AC: 62

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NEB: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2020	- -

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	-0.59	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	0.00043
Eigen_PC	Benign	0.056
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.71	T;T;T;T;.;.
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0078	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	-0.51	N;.;N;N;.;.
REVEL	Benign	0.071
Sift	Benign	0.068	T;.;T;T;.;.
Sift4G	Uncertain	0.022	D;D;D;D;D;D
Vest4		0.23
MVP		0.58
MPC		0.28
ClinPred		0.013	T
GERP RS		4.3
gMVP		0.0065

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: rs750810441; hg19: chr2-152438089;