rs78916288

Positions:

• chr2-151663544-G-A
• chr2-151663544-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.5763+4C>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 0.00204 in 1,602,128 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (29 hom.)
• Consequence: NEB NM_001164507.2 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0001986
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.66

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=-0.71).
• BP6: Variant 2-151663544-G-A is Benign according to our data. Variant chr2-151663544-G-A is described in ClinVar as [Benign]. Clinvar id is 129750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00988 (1505/152252) while in subpopulation AFR AF= 0.0334 (1387/41528). AF 95% confidence interval is 0.0319. There are 31 homozygotes in gnomad4. There are 733 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.5763+4C>T		splice_donor_region_variant, intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.5763+4C>T		splice_donor_region_variant, intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.5763+4C>T		splice_donor_region_variant, intron_variant		5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.5763+4C>T		splice_donor_region_variant, intron_variant		5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.5763+4C>T		splice_donor_region_variant, intron_variant		5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.00985 AC: 1499 AN: 152134 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0334

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00247 AC: 603 AN: 244224 Hom.: 9 AF XY: 0.00190 AC XY: 251 AN XY: 132442

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.00122 AC: 1771 AN: 1449876 Hom.: 29 Cov.: 31 AF XY: 0.00108 AC XY: 778 AN XY: 719048

Gnomad4 AFR exome AF: 0.0355

Gnomad4 AMR exome AF: 0.00211

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.0000938

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000312

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00988 AC: 1505 AN: 152252 Hom.: 31 Cov.: 32 AF XY: 0.00984 AC XY: 733 AN XY: 74458

Gnomad4 AFR AF: 0.0334

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00338 Hom.: 7

Bravo AF: 0.0114

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 20, 2023	Variant summary: NEB c.5763+4C>T alters a nonconserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence, however one in silico tool predict no impact on normal splicing. The variant allele was found at a frequency of 0.0099 in 150906 control chromosomes, predominantly within the African or African-American subpopulation at a frequency of 0.033 in the gnomAD database, including 29 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 9-fold of the estimated maximal expected allele frequency for a pathogenic variant in NEB causing Nemaline Myopathy 2 phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.5763+4C>T in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
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. -

Nemaline myopathy 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.0010
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.060
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs78916288; hg19: chr2-152520058;