rs13427102

Variant names:

• chr2-151680837-C-T
• rs13427102
• NM_001164507.2:c.2944-9G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164508.2(NEB):​c.2944-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.078 in 1,592,550 control chromosomes in the GnomAD database, including 5,549 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 0.10 (974 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4575 hom.)
• Consequence: NEB NM_001164508.2 intron
• Scores: Splicing: ADA: 0.00003707
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.09
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-151680837-C-T is Benign according to our data. Variant chr2-151680837-C-T is described in ClinVar as Benign. ClinVar VariationId is 129738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 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.2944-9G>A		intron	N/A	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.2944-9G>A		intron	N/A	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.2944-9G>A		intron	N/A	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.2944-9G>A		intron	N/A	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.2944-9G>A		intron	N/A	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.2944-9G>A		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0995 AC: 15107 AN: 151898 Hom.: 973 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.0659

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.0490

Gnomad SAS AF: 0.0667

Gnomad FIN AF: 0.0253

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.0761

Gnomad OTH AF: 0.0829

GnomAD2 exomes AF: 0.0706 AC: 17580 AN: 248918 AF XY: 0.0695

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.0406

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.0447

Gnomad FIN exome AF: 0.0272

Gnomad NFE exome AF: 0.0739

Gnomad OTH exome AF: 0.0687

GnomAD4 exome AF: 0.0758 AC: 109156 AN: 1440534 Hom.: 4575 Cov.: 28 AF XY: 0.0752 AC XY: 54022 AN XY: 718066

African (AFR) AF: 0.179 AC: 5909 AN: 33014

American (AMR) AF: 0.0434 AC: 1937 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2894 AN: 25996

East Asian (EAS) AF: 0.0517 AC: 2045 AN: 39526

South Asian (SAS) AF: 0.0672 AC: 5760 AN: 85754

European-Finnish (FIN) AF: 0.0289 AC: 1544 AN: 53362

Middle Eastern (MID) AF: 0.0871 AC: 499 AN: 5726

European-Non Finnish (NFE) AF: 0.0766 AC: 83689 AN: 1092854

Other (OTH) AF: 0.0818 AC: 4879 AN: 59658

GnomAD4 genome AF: 0.0995 AC: 15126 AN: 152016 Hom.: 974 Cov.: 32 AF XY: 0.0958 AC XY: 7121 AN XY: 74330

African (AFR) AF: 0.178 AC: 7369 AN: 41444

American (AMR) AF: 0.0658 AC: 1005 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 434 AN: 3468

East Asian (EAS) AF: 0.0487 AC: 252 AN: 5170

South Asian (SAS) AF: 0.0665 AC: 320 AN: 4810

European-Finnish (FIN) AF: 0.0253 AC: 268 AN: 10574

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.0761 AC: 5172 AN: 67960

Other (OTH) AF: 0.0821 AC: 173 AN: 2108

Alfa AF: 0.0983 Hom.: 265

Bravo AF: 0.105

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.6
DANN	Benign	0.58
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.0040
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: rs13427102; hg19: chr2-152537351; COSMIC: COSV51444142;