rs16830192

Variant names:

• chr2-151541531-G-C
• rs16830192
• NM_001164507.2:c.20598C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001164508.2(NEB):​c.20598C>G​(p.Gly6866Gly) variant causes a synonymous change. The variant allele was found at a frequency of 0.0163 in 1,613,128 control chromosomes in the GnomAD database, including 1,327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.042 (357 hom., cov: 32)
  • Exomes 𝑓: 0.014 (970 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 5.76
• Publications: 7 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen
• autosomal dominant nebulin-related myopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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

LOC124906081 (HGNC:):

ACMG classification

Specifications for NEB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 2-151541531-G-C is Benign according to our data. Variant chr2-151541531-G-C is described in ClinVar as Benign. ClinVar VariationId is 129722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164508.2. 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.20598C>G	p.Gly6866Gly	synonymous	Exon 136 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.20598C>G	p.Gly6866Gly	synonymous	Exon 136 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.20598C>G	p.Gly6866Gly	synonymous	Exon 136 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.20598C>G	p.Gly6866Gly	synonymous	Exon 136 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.20598C>G	p.Gly6866Gly	synonymous	Exon 136 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.15495C>G	p.Gly5165Gly	synonymous	Exon 109 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0420 AC: 6382 AN: 152076 Hom.: 345 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0748

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.0431

GnomAD2 exomes AF: 0.0295 AC: 7338 AN: 248604 AF XY: 0.0299

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.00861

Gnomad ASJ exome AF: 0.0322

Gnomad EAS exome AF: 0.147

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0136 AC: 19798 AN: 1460934 Hom.: 970 Cov.: 30 AF XY: 0.0149 AC XY: 10825 AN XY: 726754

African (AFR) AF: 0.117 AC: 3905 AN: 33404

American (AMR) AF: 0.00899 AC: 402 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0324 AC: 846 AN: 26112

East Asian (EAS) AF: 0.137 AC: 5439 AN: 39650

South Asian (SAS) AF: 0.0652 AC: 5614 AN: 86126

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53374

Middle Eastern (MID) AF: 0.0196 AC: 113 AN: 5766

European-Non Finnish (NFE) AF: 0.00164 AC: 1822 AN: 1111468

Other (OTH) AF: 0.0272 AC: 1638 AN: 60322

GnomAD4 genome AF: 0.0422 AC: 6419 AN: 152194 Hom.: 357 Cov.: 32 AF XY: 0.0427 AC XY: 3181 AN XY: 74422

African (AFR) AF: 0.111 AC: 4622 AN: 41500

American (AMR) AF: 0.0193 AC: 295 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3470

East Asian (EAS) AF: 0.145 AC: 753 AN: 5176

South Asian (SAS) AF: 0.0755 AC: 364 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00226 AC: 154 AN: 68010

Other (OTH) AF: 0.0531 AC: 112 AN: 2108

Alfa AF: 0.0153 Hom.: 32

Bravo AF: 0.0458

Asia WGS AF: 0.137 AC: 474 AN: 3478

EpiCase AF: 0.00377

EpiControl AF: 0.00321

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Nemaline myopathy 2 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	6.7
DANN	Benign	0.75
PhyloP100		5.8
Mutation Taster		=94/6	polymorphism (auto)

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: rs16830192; hg19: chr2-152398045; COSMIC: COSV51419688; COSMIC: COSV51419688;