rs554231162

chr2-151592075-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001164507.2(NEB):c.14785C>T(p.Leu4929=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 152,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000082 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.86

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-151592075-G-A is Benign according to our data. Variant chr2-151592075-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257744.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.14785C>T	p.Leu4929=	synonymous_variant	95/182	ENST00000427231.7
NEB	NM_001164508.2	c.14785C>T	p.Leu4929=	synonymous_variant	95/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.14785C>T	p.Leu4929=	synonymous_variant	95/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.14785C>T	p.Leu4929=	synonymous_variant	95/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.11602-15721C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152294 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000823 AC: 115 AN: 1397164 Hom.: 0 Cov.: 32 AF XY: 0.000120 AC XY: 83 AN XY: 689096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00135

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.0000692

GnomAD4 genome AF: 0.0000459 AC: 7 AN: 152412 Hom.: 0 Cov.: 30 AF XY: 0.0000268 AC XY: 2 AN XY: 74534

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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_noAF	Benign	-0.80
Cadd	Benign	0.74
Dann	Benign	0.56

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: rs554231162; hg19: chr2-152448589;