rs148095660

Variant names:

• chr2-151562719-C-T
• rs148095660
• NM_001164507.2:c.18783G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.18783G>A is a synonymous (silent) variant (p.Gln6261=) that is not predicted by SpliceAI to impact splicing. However, it occurs at a nucleotide that is conserved as shown by the UCSC Genome Browser (BP4, BP7 not met). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.02590 (2413/89448 alleles, 58 homozygotes) in the South Asian population, which is higher than the ClinGen Congenital Myopathies threshold (≥0.00559) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA203801/MONDO:0018958/146

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (60 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 0.777
• Publications: 2 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

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

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.18783G>A	p.Gln6261Gln	synonymous	Exon 120 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.18783G>A	p.Gln6261Gln	synonymous	Exon 120 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.18783G>A	p.Gln6261Gln	synonymous	Exon 120 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.18783G>A	p.Gln6261Gln	synonymous	Exon 120 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.18783G>A	p.Gln6261Gln	synonymous	Exon 120 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.13680G>A	p.Gln4560Gln	synonymous	Exon 93 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 265 AN: 152138 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00400 AC: 959 AN: 239474 AF XY: 0.00503

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.000240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00518

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.000332

Gnomad OTH exome AF: 0.00290

GnomAD4 exome AF: 0.00207 AC: 3005 AN: 1454398 Hom.: 60 Cov.: 31 AF XY: 0.00276 AC XY: 1998 AN XY: 722736

African (AFR) AF: 0.00135 AC: 45 AN: 33396

American (AMR) AF: 0.000182 AC: 8 AN: 43952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25880

East Asian (EAS) AF: 0.00294 AC: 116 AN: 39452

South Asian (SAS) AF: 0.0268 AC: 2270 AN: 84626

European-Finnish (FIN) AF: 0.000395 AC: 21 AN: 53106

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5746

European-Non Finnish (NFE) AF: 0.000325 AC: 360 AN: 1108108

Other (OTH) AF: 0.00296 AC: 178 AN: 60132

GnomAD4 genome AF: 0.00174 AC: 265 AN: 152254 Hom.: 2 Cov.: 31 AF XY: 0.00216 AC XY: 161 AN XY: 74432

African (AFR) AF: 0.00176 AC: 73 AN: 41560

American (AMR) AF: 0.000720 AC: 11 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00328 AC: 17 AN: 5184

South Asian (SAS) AF: 0.0297 AC: 143 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68016

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000768 Hom.: 1

Bravo AF: 0.00117

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	7.7
DANN	Benign	0.55
PhyloP100		0.78
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs148095660; hg19: chr2-152419233;