rs62167164

chr2-151537930-G-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.21044C>G(p.Ser7015Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,300 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (11 hom., cov: 32)
  • Exomes 𝑓: 0.011 (95 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 9.60

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]

LOC124906081 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008066177).
• BP6: Variant 2-151537930-G-C is Benign according to our data. Variant chr2-151537930-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 129724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151537930-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00902 (1374/152248) while in subpopulation NFE AF= 0.013 (886/68022). AF 95% confidence interval is 0.0123. There are 11 homozygotes in gnomad4. There are 704 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.21044C>G	p.Ser7015Cys	missense_variant	140/182	ENST00000427231.7
NEB	NM_001164508.2	c.21044C>G	p.Ser7015Cys	missense_variant	140/182	ENST00000397345.8
LOC124906081	XR_007087266.1	n.155G>C		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.21044C>G	p.Ser7015Cys	missense_variant	140/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.21044C>G	p.Ser7015Cys	missense_variant	140/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.00903 AC: 1373 AN: 152130 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0276

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00892 AC: 2217 AN: 248626 Hom.: 18 AF XY: 0.00915 AC XY: 1234 AN XY: 134832

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00707

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00390

Gnomad FIN exome AF: 0.0234

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.00977

GnomAD4 exome AF: 0.0107 AC: 15671 AN: 1461052 Hom.: 95 Cov.: 30 AF XY: 0.0107 AC XY: 7792 AN XY: 726776

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00716

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00376

Gnomad4 FIN exome AF: 0.0221

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.00991

GnomAD4 genome AF: 0.00902 AC: 1374 AN: 152248 Hom.: 11 Cov.: 32 AF XY: 0.00946 AC XY: 704 AN XY: 74426

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0276

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.0113 Hom.: 10

Bravo AF: 0.00677

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00161 AC: 6

ESP6500EA AF: 0.0118 AC: 97

ExAC AF: 0.00899 AC: 1086

EpiCase AF: 0.0119

EpiControl AF: 0.0120

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 16, 2017	- -

Nemaline myopathy 2 Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

NEB: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T;T;T;T;T;D;.;.;D
MetaRNN	Benign	0.0081	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;.;.;.;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	D;N;.;N;D;N;.;.;N
REVEL	Benign	0.26
Sift	Benign	0.37	T;T;.;T;T;T;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;T;D;D;.
Polyphen		1.0	.;.;.;.;D;.;.;.;.
Vest4		0.76
MVP		0.55
MPC		0.34
ClinPred		0.029	T
GERP RS		5.6
Varity_R		0.34
gMVP		0.47

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: rs62167164; hg19: chr2-152394444; COSMIC: COSV51453522;