chr2-151664582-C-T

Variant names:

• chr2-151664582-C-T
• rs10170273
• NM_001164507.2:c.5370G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001164508.2(NEB):​c.5370G>A​(p.Glu1790Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,604,590 control chromosomes in the GnomAD database, including 47,250 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (10269 hom., cov: 33)
  • Exomes 𝑓: 0.19 (36981 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.319
• Publications: 20 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-151664582-C-T is Benign according to our data. Variant chr2-151664582-C-T is described in ClinVar as Benign. ClinVar VariationId is 129746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.319 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.593 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.5370G>A	p.Glu1790Glu	synonymous	Exon 44 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.5370G>A	p.Glu1790Glu	synonymous	Exon 44 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.5370G>A	p.Glu1790Glu	synonymous	Exon 44 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.5370G>A	p.Glu1790Glu	synonymous	Exon 44 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.5370G>A	p.Glu1790Glu	synonymous	Exon 44 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.5370G>A	p.Glu1790Glu	synonymous	Exon 44 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46248 AN: 152036 Hom.: 10216 Cov.: 33

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.277

GnomAD2 exomes AF: 0.235 AC: 55160 AN: 234970 AF XY: 0.233

Gnomad AFR exome AF: 0.605

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.246

Gnomad EAS exome AF: 0.582

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.194 AC: 282020 AN: 1452434 Hom.: 36981 Cov.: 32 AF XY: 0.197 AC XY: 142009 AN XY: 721562

African (AFR) AF: 0.616 AC: 20458 AN: 33206

American (AMR) AF: 0.139 AC: 6087 AN: 43696

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 6457 AN: 25840

East Asian (EAS) AF: 0.619 AC: 24390 AN: 39420

South Asian (SAS) AF: 0.333 AC: 28086 AN: 84238

European-Finnish (FIN) AF: 0.141 AC: 7478 AN: 53014

Middle Eastern (MID) AF: 0.225 AC: 1287 AN: 5732

European-Non Finnish (NFE) AF: 0.157 AC: 173521 AN: 1107266

Other (OTH) AF: 0.238 AC: 14256 AN: 60022

GnomAD4 genome AF: 0.305 AC: 46355 AN: 152156 Hom.: 10269 Cov.: 33 AF XY: 0.302 AC XY: 22480 AN XY: 74382

African (AFR) AF: 0.599 AC: 24871 AN: 41492

American (AMR) AF: 0.183 AC: 2797 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 905 AN: 3468

East Asian (EAS) AF: 0.605 AC: 3133 AN: 5178

South Asian (SAS) AF: 0.341 AC: 1645 AN: 4824

European-Finnish (FIN) AF: 0.131 AC: 1394 AN: 10604

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10786 AN: 67988

Other (OTH) AF: 0.285 AC: 603 AN: 2116

Alfa AF: 0.204 Hom.: 7374

Bravo AF: 0.320

Asia WGS AF: 0.542 AC: 1879 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Nemaline myopathy 2 (4)
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	2.5
DANN	Benign	0.52
PhyloP100		-0.32
Mutation Taster		=99/1	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: rs10170273; hg19: chr2-152521096; COSMIC: COSV50874015; COSMIC: COSV50874015;