2-151582622-A-G

Position:

• chr2-151582622-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_001164507.2(NEB):​c.16021T>C​(p.Leu5341=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (10 hom., cov: 0)
  • Exomes 𝑓: 0.19 (1608 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.629

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 2-151582622-A-G is Benign according to our data. Variant chr2-151582622-A-G is described in ClinVar as [Benign]. Clinvar id is 257756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151582622-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.629 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.16021T>C	p.Leu5341=	synonymous_variant	102/182	ENST00000427231.7
NEB	NM_001164508.2	c.16021T>C	p.Leu5341=	synonymous_variant	102/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.16021T>C	p.Leu5341=	synonymous_variant	102/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.16021T>C	p.Leu5341=	synonymous_variant	102/182	5	NM_001164507.2	A2
NEB	ENST00000413693.5	c.211T>C	p.Leu71=	synonymous_variant	2/74	5
NEB	ENST00000409198.5	c.11602-6268T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 166 AN: 880 Hom.: 10 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.246

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0625

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.273

GnomAD3 exomes AF: 0.0202 AC: 5 AN: 248 Hom.: 0 AF XY: 0.0149 AC XY: 2 AN XY: 134

Gnomad AFR exome AF: 0.0556

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0556

Gnomad SAS exome AF: 0.0143

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.0833

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.192 AC: 14892 AN: 77562 Hom.: 1608 Cov.: 0 AF XY: 0.184 AC XY: 7664 AN XY: 41720

Gnomad4 AFR exome AF: 0.294

Gnomad4 AMR exome AF: 0.223

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.300

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.215

Gnomad4 NFE exome AF: 0.187

Gnomad4 OTH exome AF: 0.193

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.190 AC: 169 AN: 890 Hom.: 10 Cov.: 0 AF XY: 0.186 AC XY: 73 AN XY: 392

Gnomad4 AFR AF: 0.247

Gnomad4 AMR AF: 0.188

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.286

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0625

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.250

Alfa AF: 0.194 Hom.: 251

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

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_noAF	Benign	-0.27
CADD	Benign	9.4
DANN	Benign	0.89

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: rs796103760; hg19: chr2-152439136;