rs146310692

Positions:

• chr2-151662137-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BS1 BS2_Supporting

The NM_001164507.2(NEB):​c.5968G>A​(p.Glu1990Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,609,152 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (3 hom.)
• Consequence: NEB NM_001164507.2 missense, splice_region
• Scores: Splicing: ADA: 0.0001490
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.904

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042778254).
• BP6: Variant 2-151662137-C-T is Benign according to our data. Variant chr2-151662137-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 331500.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 = 0.00287 (437/152250) while in subpopulation AFR AF= 0.0098 (407/41544). AF 95% confidence interval is 0.00901. There are 1 homozygotes in gnomad4. There are 197 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.5968G>A	p.Glu1990Lys	missense_variant, splice_region_variant	46/182	ENST00000427231.7
NEB	NM_001164508.2	c.5968G>A	p.Glu1990Lys	missense_variant, splice_region_variant	46/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.5968G>A	p.Glu1990Lys	missense_variant, splice_region_variant	46/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.5968G>A	p.Glu1990Lys	missense_variant, splice_region_variant	46/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.5968G>A	p.Glu1990Lys	missense_variant, splice_region_variant	46/150	5

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 437 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00983

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000680 AC: 168 AN: 247198 Hom.: 1 AF XY: 0.000582 AC XY: 78 AN XY: 134114

Gnomad AFR exome AF: 0.00947

Gnomad AMR exome AF: 0.000467

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000321 AC: 468 AN: 1456902 Hom.: 3 Cov.: 30 AF XY: 0.000270 AC XY: 196 AN XY: 724704

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.000516

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000325

Gnomad4 OTH exome AF: 0.000765

GnomAD4 genome AF: 0.00287 AC: 437 AN: 152250 Hom.: 1 Cov.: 32 AF XY: 0.00265 AC XY: 197 AN XY: 74438

Gnomad4 AFR AF: 0.00980

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000542 Hom.: 0

Bravo AF: 0.00337

ESP6500AA AF: 0.00823 AC: 31

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000836 AC: 101

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	NEB: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2021	- -

Nemaline myopathy 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 08, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Benign	0.96
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;.;.
MetaRNN	Benign	0.0043	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.32	N;N;.;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.67	N;N;.;N;N;.;.
REVEL	Benign	0.064
Sift	Benign	0.61	T;T;.;T;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0060	.;.;.;.;B;.;.
Vest4		0.27
MVP		0.28
MPC		0.058
ClinPred		0.0047	T
GERP RS		3.8
Varity_R		0.065
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
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: rs146310692; hg19: chr2-152518651; COSMIC: COSV51161144;