rs192098032

chr2-151636277-C-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.9052G>A(p.Asp3018Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000754 in 1,610,202 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D3018Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (14 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.54

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 (MetaRNN=0.010050595).
• BP6: Variant 2-151636277-C-T is Benign according to our data. Variant chr2-151636277-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00104 (158/152340) while in subpopulation EAS AF= 0.0256 (133/5194). AF 95% confidence interval is 0.0221. There are 3 homozygotes in gnomad4. There are 94 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.9052G>A	p.Asp3018Asn	missense_variant	64/182	ENST00000427231.7
NEB	NM_001164508.2	c.9052G>A	p.Asp3018Asn	missense_variant	64/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.9052G>A	p.Asp3018Asn	missense_variant	64/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.9052G>A	p.Asp3018Asn	missense_variant	64/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.8853+3616G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152222 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0259

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00255 AC: 629 AN: 246288 Hom.: 10 AF XY: 0.00236 AC XY: 316 AN XY: 133884

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0342

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000830

GnomAD4 exome AF: 0.000724 AC: 1056 AN: 1457862 Hom.: 14 Cov.: 31 AF XY: 0.000702 AC XY: 509 AN XY: 725338

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0217

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152340 Hom.: 3 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74500

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0256

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00141 Hom.: 3

Bravo AF: 0.00125

ExAC AF: 0.00222 AC: 268

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 24, 2017	Variant summary: The c.9052G>A (p.Asp3018Asn) in NEB gene is a missense change that alters a conserved nucleotide and 4/4 in silico tools predict damaging outcome. The variant is located within conserved nebulin repeats, although the impact of this change is yet to be confirmed by functional studies. The variant is present in the large control population datasets of ExAC and gnomAD at similar frequency (264/117446 chrs and 668/274324 chrs, respectively), predominantly East Asian sub-population [0.0310 (257/8286 chrs) in ExAC and 0.03452 (648/18770 chrs tested, including 10 homozygotes) in gnomAD]. These frequencies exceed the estimated maximal expected allele frequency of a pathogenic variant in NEB gene (0.0035). This variant has been reported in two siblings from a family with nemaline myopathy in compound heterozygous state with p.Ser8228Ser (Chen_2013); whether this genotype explained the phenotype in the family is unknown. Lastly, a reputable database/diagnostic center has classified the variant of interest as benign. Taken together, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 27, 2019	- -

Nemaline myopathy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;.;.
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-2.1	N;.;N;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D;.;D;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D
Vest4		0.72
MVP		0.53
MPC		0.34
ClinPred		0.062	T
GERP RS		6.0
gMVP		0.14

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: rs192098032; hg19: chr2-152492791; COSMIC: COSV50837184;