rs200602229

Positions:

• chr2-151579500-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001164508.2(NEB):​c.16542C>G​(p.Ala5514Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,492,632 control chromosomes in the GnomAD database, including 923 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (103 hom., cov: 15)
  • Exomes 𝑓: 0.0097 (820 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.16

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=-0.53).
• BP6: Variant 2-151579500-G-C is Benign according to our data. Variant chr2-151579500-G-C is described in ClinVar as [Benign]. Clinvar id is 257763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151579500-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.16542C>G	p.Ala5514Ala	synonymous_variant	105/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.16542C>G	p.Ala5514Ala	synonymous_variant	105/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.16542C>G	p.Ala5514Ala	synonymous_variant	105/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.16542C>G	p.Ala5514Ala	synonymous_variant	105/182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000413693.5	c.732C>G	p.Ala244Ala	synonymous_variant	5/74	5		ENSP00000410961.1
NEB	ENST00000409198.5	c.11602-3146C>G		intron_variant		5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2319 AN: 122916 Hom.: 97 Cov.: 15

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.0345

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.0529

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0142

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.0288

GnomAD3 exomes AF: 0.0316 AC: 1928 AN: 60978 Hom.: 139 AF XY: 0.0331 AC XY: 1008 AN XY: 30424

Gnomad AFR exome AF: 0.0330

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.0406

Gnomad EAS exome AF: 0.149

Gnomad SAS exome AF: 0.0498

Gnomad FIN exome AF: 0.000243

Gnomad NFE exome AF: 0.00278

Gnomad OTH exome AF: 0.0234

GnomAD4 exome AF: 0.00973 AC: 13325 AN: 1369628 Hom.: 820 Cov.: 29 AF XY: 0.0109 AC XY: 7359 AN XY: 676484

Gnomad4 AFR exome AF: 0.0315

Gnomad4 AMR exome AF: 0.00376

Gnomad4 ASJ exome AF: 0.0330

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.0473

Gnomad4 FIN exome AF: 0.000286

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.0201

GnomAD4 genome AF: 0.0191 AC: 2347 AN: 123004 Hom.: 103 Cov.: 15 AF XY: 0.0199 AC XY: 1159 AN XY: 58346

Gnomad4 AFR AF: 0.0302

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.0345

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.0537

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.0373

Alfa AF: 0.0121 Hom.: 4

Bravo AF: 0.0185

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.5
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200602229; hg19: chr2-152436014; COSMIC: COSV51421666;