rs141930814

Variant names:

• chr2-151663744-C-T
• rs141930814
• NM_001164507.2:c.5567G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001271208.2(NEB):​c.5567G>A​(p.Arg1856Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,613,756 control chromosomes in the GnomAD database, including 187 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. R1856W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 32)
  • Exomes 𝑓: 0.014 (173 hom.)
• Consequence: NEB NM_001271208.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.27
• Publications: 6 publications found

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]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007861137).
• BP6: Variant 2-151663744-C-T is Benign according to our data. Variant chr2-151663744-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0104 (1581/152270) while in subpopulation NFE AF = 0.017 (1155/68020). AF 95% confidence interval is 0.0162. There are 14 homozygotes in GnomAd4. There are 755 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271208.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.5567G>A	p.Arg1856Gln	missense	Exon 45 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.5567G>A	p.Arg1856Gln	missense	Exon 45 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.5567G>A	p.Arg1856Gln	missense	Exon 45 of 183	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.5567G>A	p.Arg1856Gln	missense	Exon 45 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.5567G>A	p.Arg1856Gln	missense	Exon 45 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.5567G>A	p.Arg1856Gln	missense	Exon 45 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1582 AN: 152152 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.0105 AC: 2621 AN: 248952 AF XY: 0.0105

Gnomad AFR exome AF: 0.00233

Gnomad AMR exome AF: 0.00473

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0141 AC: 20585 AN: 1461486 Hom.: 173 Cov.: 31 AF XY: 0.0139 AC XY: 10078 AN XY: 727024

African (AFR) AF: 0.00200 AC: 67 AN: 33466

American (AMR) AF: 0.00465 AC: 208 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00364 AC: 95 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39692

South Asian (SAS) AF: 0.00398 AC: 343 AN: 86254

European-Finnish (FIN) AF: 0.0126 AC: 673 AN: 53380

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5766

European-Non Finnish (NFE) AF: 0.0166 AC: 18441 AN: 1111752

Other (OTH) AF: 0.0123 AC: 740 AN: 60358

GnomAD4 genome AF: 0.0104 AC: 1581 AN: 152270 Hom.: 14 Cov.: 32 AF XY: 0.0101 AC XY: 755 AN XY: 74456

African (AFR) AF: 0.00238 AC: 99 AN: 41558

American (AMR) AF: 0.0107 AC: 163 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4830

European-Finnish (FIN) AF: 0.0114 AC: 121 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0170 AC: 1155 AN: 68020

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.0151 Hom.: 68

Bravo AF: 0.00934

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00326 AC: 13

ESP6500EA AF: 0.0165 AC: 138

ExAC AF: 0.0106 AC: 1281

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0151

EpiControl AF: 0.0136

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Nemaline myopathy 2 (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.18
Sift	Benign	0.042	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.35
MPC		0.18
ClinPred		0.040	T
GERP RS		5.5
Varity_R		0.24
gMVP		0.31
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs141930814; hg19: chr2-152520258; COSMIC: COSV50834125; COSMIC: COSV50834125;