rs35707762

chr2-151548387-G-A

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.20078C>T(p.Thr6693Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0103 in 1,613,528 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T6693T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0072 (12 hom., cov: 32)
  • Exomes 𝑓: 0.011 (109 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.36

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=0.0039313436).
• BP6: Variant 2-151548387-G-A is Benign according to our data. Variant chr2-151548387-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151548387-G-A is described in Lovd as [Benign]. Variant chr2-151548387-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00725 (1104/152304) while in subpopulation NFE AF= 0.0117 (795/68022). AF 95% confidence interval is 0.011. There are 12 homozygotes in gnomad4. There are 499 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.20078C>T	p.Thr6693Ile	missense_variant	131/182	ENST00000427231.7
NEB	NM_001164508.2	c.20078C>T	p.Thr6693Ile	missense_variant	131/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.20078C>T	p.Thr6693Ile	missense_variant	131/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.20078C>T	p.Thr6693Ile	missense_variant	131/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.00726 AC: 1105 AN: 152186 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00989

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00714 AC: 1778 AN: 248948 Hom.: 13 AF XY: 0.00738 AC XY: 997 AN XY: 135042

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00701

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00441

Gnomad FIN exome AF: 0.000835

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00861

GnomAD4 exome AF: 0.0106 AC: 15493 AN: 1461224 Hom.: 109 Cov.: 30 AF XY: 0.0103 AC XY: 7478 AN XY: 726910

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00751

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00463

Gnomad4 FIN exome AF: 0.00142

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.00785

GnomAD4 genome AF: 0.00725 AC: 1104 AN: 152304 Hom.: 12 Cov.: 32 AF XY: 0.00670 AC XY: 499 AN XY: 74478

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.00988

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.0117

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.0104 Hom.: 14

Bravo AF: 0.00762

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.00237 AC: 9

ESP6500EA AF: 0.0119 AC: 98

ExAC AF: 0.00682 AC: 824

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00976

EpiControl AF: 0.00895

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 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	Genetic Services Laboratory, University of Chicago	Jun 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NEB: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Nemaline myopathy 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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.	Dec 05, 2019	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	17
Dann	Benign	0.73
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.59	T;T;T;T;T;T;.;.
MetaRNN	Benign	0.0039	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N;.;.;.;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.65	N;N;.;N;N;N;.;.
REVEL	Benign	0.19
Sift	Benign	0.71	T;T;.;T;T;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;B;.;.;.
Vest4		0.18
MVP		0.36
MPC		0.054
ClinPred		0.0040	T
GERP RS		4.9
Varity_R		0.040
gMVP		0.13

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: rs35707762; hg19: chr2-152404901; COSMIC: COSV51464913;