rs141088433

Positions:

• chr2-151626996-G-A
• chr2-151626996-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):​c.10347+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,613,470 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 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00001449
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.763

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-151626996-G-A is Benign according to our data. Variant chr2-151626996-G-A is described in ClinVar as [Benign]. Clinvar id is 257718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151626996-G-A is described in Lovd as [Benign]. Variant chr2-151626996-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0088 (1340/152244) while in subpopulation EAS AF= 0.0521 (270/5186). AF 95% confidence interval is 0.047. There are 10 homozygotes in gnomad4. There are 673 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	UniProt
NEB	NM_001164507.2	c.10347+6C>T		splice_donor_region_variant, intron_variant		ENST00000427231.7
NEB	NM_001164508.2	c.10347+6C>T		splice_donor_region_variant, intron_variant		ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.10347+6C>T		splice_donor_region_variant, intron_variant		5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.10347+6C>T		splice_donor_region_variant, intron_variant		5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.9618+6C>T		splice_donor_region_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00879 AC: 1337 AN: 152126 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00675

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0529

Gnomad SAS AF: 0.00414

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: 1915 AN: 248838 Hom.: 35 AF XY: 0.00682 AC XY: 921 AN XY: 134968

Gnomad AFR exome AF: 0.0231

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0548

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: 0.00255 AC: 3733 AN: 1461226 Hom.: 67 Cov.: 31 AF XY: 0.00244 AC XY: 1777 AN XY: 726878

Gnomad4 AFR exome AF: 0.0238

Gnomad4 AMR exome AF: 0.0113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0408

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: 1340 AN: 152244 Hom.: 10 Cov.: 32 AF XY: 0.00904 AC XY: 673 AN XY: 74442

Gnomad4 AFR AF: 0.0222

Gnomad4 AMR AF: 0.00674

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0521

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00384 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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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.10347+6C>T variant involves the alteration of a non-conserved intronic nucleotide and 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 925/120680 control chromosomes (19 homozygotes) at a frequency of 0.0076649, 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 5.4% (464/8590 chromosomes). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Therefore, the variant of interest has been 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	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 2 Benign:2

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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.81
DANN	Benign	0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
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: rs141088433; hg19: chr2-152483510;