rs77151072

Positions:

• chr2-151688389-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164508.2(NEB):​c.2318A>G​(p.Tyr773Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00193 in 1,613,216 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (63 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.21

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=0.0075781643).
• BP6: Variant 2-151688389-T-C is Benign according to our data. Variant chr2-151688389-T-C is described in ClinVar as [Benign]. Clinvar id is 257795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151688389-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.057 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.2318A>G	p.Tyr773Cys	missense_variant	25/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.2318A>G	p.Tyr773Cys	missense_variant	25/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.2318A>G	p.Tyr773Cys	missense_variant	25/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.2318A>G	p.Tyr773Cys	missense_variant	25/182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.2318A>G	p.Tyr773Cys	missense_variant	25/150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 368 AN: 152260 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0625

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00501 AC: 1246 AN: 248634 Hom.: 27 AF XY: 0.00456 AC XY: 615 AN XY: 134878

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0635

Gnomad SAS exome AF: 0.00184

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00365

GnomAD4 exome AF: 0.00188 AC: 2749 AN: 1460838 Hom.: 63 Cov.: 29 AF XY: 0.00193 AC XY: 1406 AN XY: 726750

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0538

Gnomad4 SAS exome AF: 0.00244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000115

Gnomad4 OTH exome AF: 0.00423

GnomAD4 genome AF: 0.00242 AC: 369 AN: 152378 Hom.: 14 Cov.: 32 AF XY: 0.00275 AC XY: 205 AN XY: 74516

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0626

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00243 Hom.: 15

Bravo AF: 0.00255

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00502 AC: 606

Asia WGS AF: 0.0380 AC: 133 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 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	Eurofins Ntd Llc (ga)	Aug 28, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 2 Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;.;T;.;D;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.;.
MetaRNN	Benign	0.0076	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M;M;.;M;M;M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.3	D;D;.;D;D;.;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D;D;.;D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.85
MVP		0.55
MPC		0.37
ClinPred		0.038	T
GERP RS		5.7
Varity_R		0.25
gMVP		0.70

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: rs77151072; hg19: chr2-152544903; COSMIC: COSV50812737; COSMIC: COSV50812737;