rs199969138

Positions:

• chr2-151709707-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_001164507.2(NEB):​c.984C>T​(p.Thr328=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00097 in 1,605,908 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -4.09

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 2-151709707-G-A is Benign according to our data. Variant chr2-151709707-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 331538.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-4.09 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.984C>T	p.Thr328=	synonymous_variant	12/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.984C>T	p.Thr328=	synonymous_variant	12/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.984C>T	p.Thr328=	synonymous_variant	12/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.984C>T	p.Thr328=	synonymous_variant	12/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.984C>T	p.Thr328=	synonymous_variant	12/150	5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.000442 AC: 105 AN: 237500 Hom.: 0 AF XY: 0.000444 AC XY: 57 AN XY: 128318

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.000180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000349

Gnomad FIN exome AF: 0.0000477

Gnomad NFE exome AF: 0.000862

Gnomad OTH exome AF: 0.000514

GnomAD4 exome AF: 0.00102 AC: 1479 AN: 1453908 Hom.: 1 Cov.: 30 AF XY: 0.000951 AC XY: 687 AN XY: 722312

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000160

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000355

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.000513 AC: 78 AN: 152000 Hom.: 0 Cov.: 32 AF XY: 0.000566 AC XY: 42 AN XY: 74234

Gnomad4 AFR AF: 0.000218

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000971

Gnomad4 OTH AF: 0.000961

Alfa AF: 0.000883 Hom.: 0

Bravo AF: 0.000555

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 27, 2020	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 08, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	NEB: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.19
DANN	Benign	0.69

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: rs199969138; hg19: chr2-152566221;