rs147569843

Positions:

• chr2-151627011-A-G

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.10338T>C​(p.Asn3446=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,613,950 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (67 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.13

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 2-151627011-A-G is Benign according to our data. Variant chr2-151627011-A-G is described in ClinVar as [Benign]. Clinvar id is 257716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151627011-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0088 (1341/152314) while in subpopulation EAS AF= 0.0521 (270/5182). AF 95% confidence interval is 0.047. There are 10 homozygotes in gnomad4. There are 675 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.10338T>C	p.Asn3446=	synonymous_variant	70/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.10338T>C	p.Asn3446=	synonymous_variant	70/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.10338T>C	p.Asn3446=	synonymous_variant	70/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.10338T>C	p.Asn3446=	synonymous_variant	70/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.9609T>C	p.Asn3203=	synonymous_variant	67/150	5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.00879 AC: 1338 AN: 152196 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0529

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00770 AC: 1918 AN: 249122 Hom.: 35 AF XY: 0.00682 AC XY: 922 AN XY: 135142

Gnomad AFR exome AF: 0.0231

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0549

Gnomad SAS exome AF: 0.00376

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00447

GnomAD4 exome AF: 0.00256 AC: 3735 AN: 1461636 Hom.: 67 Cov.: 31 AF XY: 0.00244 AC XY: 1777 AN XY: 727106

Gnomad4 AFR exome AF: 0.0239

Gnomad4 AMR exome AF: 0.0113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0407

Gnomad4 SAS exome AF: 0.00369

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000114

Gnomad4 OTH exome AF: 0.00570

GnomAD4 genome AF: 0.00880 AC: 1341 AN: 152314 Hom.: 10 Cov.: 32 AF XY: 0.00906 AC XY: 675 AN XY: 74476

Gnomad4 AFR AF: 0.0222

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0521

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00280 Hom.: 3

Bravo AF: 0.0111

Asia WGS AF: 0.0160 AC: 56 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 24, 2017	Variant summary: The NEB c.10338T>C (p.Asn3446Asn) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts the creation of SRp40 binding site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 926/120706 control chromosomes (19 homozygotes) from ExAC at a frequency of 0.0076715, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this variant is likely a benign polymorphism. The variant is more common in East Asian population with allele frequency of 5.4% (465/8592 chromosomes). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 27, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nemaline myopathy 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 20, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 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	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.97
DANN	Benign	0.49

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: rs147569843; hg19: chr2-152483525; COSMIC: COSV105041032;