rs146294986

chr2-151562641-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001164507.2(NEB):c.18861C>T(p.Arg6287=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000564 in 1,583,948 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00035 (3 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.85

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-151562641-G-A is Benign according to our data. Variant chr2-151562641-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151562641-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00262 (399/152196) while in subpopulation AFR AF= 0.00881 (366/41532). AF 95% confidence interval is 0.00807. There are 3 homozygotes in gnomad4. There are 203 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.18861C>T	p.Arg6287=	synonymous_variant	120/182	ENST00000427231.7
NEB	NM_001164508.2	c.18861C>T	p.Arg6287=	synonymous_variant	120/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.18861C>T	p.Arg6287=	synonymous_variant	120/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.18861C>T	p.Arg6287=	synonymous_variant	120/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152080 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00867

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000720 AC: 176 AN: 244538 Hom.: 0 AF XY: 0.000642 AC XY: 85 AN XY: 132498

Gnomad AFR exome AF: 0.00813

Gnomad AMR exome AF: 0.000532

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000338

Gnomad SAS exome AF: 0.000169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.000844

GnomAD4 exome AF: 0.000345 AC: 494 AN: 1431752 Hom.: 3 Cov.: 30 AF XY: 0.000345 AC XY: 244 AN XY: 706814

Gnomad4 AFR exome AF: 0.00934

Gnomad4 AMR exome AF: 0.000659

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000128

Gnomad4 SAS exome AF: 0.000228

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000606

Gnomad4 OTH exome AF: 0.000916

GnomAD4 genome AF: 0.00262 AC: 399 AN: 152196 Hom.: 3 Cov.: 31 AF XY: 0.00273 AC XY: 203 AN XY: 74400

Gnomad4 AFR AF: 0.00881

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.00284

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -

Nemaline myopathy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.35
Dann	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs146294986; hg19: chr2-152419155;