2-151563606-C-G

Position:

• chr2-151563606-C-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):​c.18693G>C​(p.Ala6231=) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,611,602 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (11 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (38 hom.)
• Consequence: NEB NM_001164507.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.9982
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 7.63

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 -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 2-151563606-C-G is Benign according to our data. Variant chr2-151563606-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 129714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151563606-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00481 (733/152292) while in subpopulation EAS AF= 0.0454 (235/5178). AF 95% confidence interval is 0.0406. There are 11 homozygotes in gnomad4. There are 379 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.18693G>C	p.Ala6231=	splice_region_variant, synonymous_variant	119/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.18693G>C	p.Ala6231=	splice_region_variant, synonymous_variant	119/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.18693G>C	p.Ala6231=	splice_region_variant, synonymous_variant	119/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.18693G>C	p.Ala6231=	splice_region_variant, synonymous_variant	119/182	5	NM_001164507.2	ENSP00000416578	A2

Frequencies

GnomAD3 genomes AF: 0.00480 AC: 730 AN: 152174 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00910

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0461

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00619 AC: 1541 AN: 248958 Hom.: 26 AF XY: 0.00578 AC XY: 781 AN XY: 135038

Gnomad AFR exome AF: 0.00846

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0494

Gnomad SAS exome AF: 0.00363

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000222

Gnomad OTH exome AF: 0.00331

GnomAD4 exome AF: 0.00186 AC: 2720 AN: 1459310 Hom.: 38 Cov.: 30 AF XY: 0.00183 AC XY: 1332 AN XY: 726140

Gnomad4 AFR exome AF: 0.00907

Gnomad4 AMR exome AF: 0.00997

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0314

Gnomad4 SAS exome AF: 0.00365

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000982

Gnomad4 OTH exome AF: 0.00484

GnomAD4 genome AF: 0.00481 AC: 733 AN: 152292 Hom.: 11 Cov.: 31 AF XY: 0.00509 AC XY: 379 AN XY: 74446

Gnomad4 AFR AF: 0.00924

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0454

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00163 Hom.: 2

Bravo AF: 0.00589

Asia WGS AF: 0.0170 AC: 58 AN: 3476

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

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)	-	- -
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.18693G>C (p.Ala6231Ala) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change that is located at the last nucleotide of exon 119, therefore suggesting the variant could affect splicing. One in silico tool (mutation taster) predicts a damaging outcome for this variant. 3/5 splice prediction tools predict an impact on normal splicing and ESE finder predicts that this variant may affect ESE site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 703/120702 control chromosomes (16 homozygotes) from ExAC at a frequency of 0.0058243, 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 sub-population with allele frequency of 4.7% (408/8614 chromosomes). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/benign." Therefore, the variant of interest has been classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 27, 2019	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
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	Eurofins Ntd Llc (ga)	Feb 13, 2015	- -

Nemaline myopathy 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	- -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.15		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: rs141338915; hg19: chr2-152420120;