rs35740585

Positions:

• chr2-151612262-T-C

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.11729A>G​(p.Asp3910Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,613,868 control chromosomes in the GnomAD database, including 360 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. D3910E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (32 hom., cov: 32)
  • Exomes 𝑓: 0.020 (328 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.62

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=0.004578173).
• BP6: Variant 2-151612262-T-C is Benign according to our data. Variant chr2-151612262-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 129707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151612262-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.014 (2125/152296) while in subpopulation NFE AF= 0.0217 (1477/68026). AF 95% confidence interval is 0.0208. There are 32 homozygotes in gnomad4. There are 1035 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.11729A>G	p.Asp3910Gly	missense_variant	78/182	ENST00000427231.7
NEB	NM_001164508.2	c.11729A>G	p.Asp3910Gly	missense_variant	78/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.11729A>G	p.Asp3910Gly	missense_variant	78/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.11729A>G	p.Asp3910Gly	missense_variant	78/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.11000A>G	p.Asp3667Gly	missense_variant	75/150	5

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2126 AN: 152178 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.0147 AC: 3658 AN: 248950 Hom.: 41 AF XY: 0.0144 AC XY: 1939 AN XY: 135046

Gnomad AFR exome AF: 0.00342

Gnomad AMR exome AF: 0.00678

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00490

Gnomad FIN exome AF: 0.0266

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0164

GnomAD4 exome AF: 0.0196 AC: 28596 AN: 1461572 Hom.: 328 Cov.: 31 AF XY: 0.0190 AC XY: 13824 AN XY: 727088

Gnomad4 AFR exome AF: 0.00379

Gnomad4 AMR exome AF: 0.00631

Gnomad4 ASJ exome AF: 0.00425

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00489

Gnomad4 FIN exome AF: 0.0285

Gnomad4 NFE exome AF: 0.0226

Gnomad4 OTH exome AF: 0.0160

GnomAD4 genome AF: 0.0140 AC: 2125 AN: 152296 Hom.: 32 Cov.: 32 AF XY: 0.0139 AC XY: 1035 AN XY: 74470

Gnomad4 AFR AF: 0.00419

Gnomad4 AMR AF: 0.00745

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.0282

Gnomad4 NFE AF: 0.0217

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0193 Hom.: 57

Bravo AF: 0.0122

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00430 AC: 17

ESP6500EA AF: 0.0229 AC: 192

ExAC AF: 0.0149 AC: 1799

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0192

EpiControl AF: 0.0187

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 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	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 24, 2020	- -

Nemaline myopathy 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 28, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	.;.;T;.;T;.;.
Eigen	Benign	0.048
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.83	T;T;T;T;T;.;.
MetaRNN	Benign	0.0046	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M;.;.;.;M;.;.
MutationTaster	Benign	0.63	N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.0	N;D;.;D;N;.;.
REVEL	Benign	0.14
Sift	Uncertain	0.029	D;T;.;T;D;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D
Polyphen		0.49	.;.;.;.;P;.;.
Vest4		0.38
MPC		0.094
ClinPred		0.020	T
GERP RS		3.1
Varity_R		0.11
gMVP		0.41

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: rs35740585; hg19: chr2-152468776;