rs116189169

Variant names:

• chr2-151563817-A-G
• rs116189169
• NM_001164507.2:c.18579+6T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-151563817-A-G
• chr2-151563817-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS1

The NM_001164508.2(NEB):​c.18579+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000318 in 1,611,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: NEB NM_001164508.2 splice_region, intron
• Scores: Splicing: ADA: 0.5187
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: 1.83
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 2-151563817-A-G is Benign according to our data. Variant chr2-151563817-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 465520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00163 (248/152324) while in subpopulation AFR AF = 0.00531 (221/41582). AF 95% confidence interval is 0.00474. There are 0 homozygotes in GnomAd4. There are 115 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.18579+6T>C		splice_region intron	N/A	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.18579+6T>C		splice_region intron	N/A	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.18579+6T>C		splice_region 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.18579+6T>C		splice_region intron	N/A	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.18579+6T>C		splice_region intron	N/A	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.13476+6T>C		splice_region intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 247 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000375 AC: 93 AN: 248162 AF XY: 0.000357

Gnomad AFR exome AF: 0.00557

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000181 AC: 264 AN: 1459200 Hom.: 0 Cov.: 31 AF XY: 0.000164 AC XY: 119 AN XY: 726074

African (AFR) AF: 0.00587 AC: 196 AN: 33402

American (AMR) AF: 0.000358 AC: 16 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.00000991 AC: 11 AN: 1109780

Other (OTH) AF: 0.000564 AC: 34 AN: 60282

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74482

African (AFR) AF: 0.00531 AC: 221 AN: 41582

American (AMR) AF: 0.00124 AC: 19 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000863 Hom.: 0

Bravo AF: 0.00188

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	NEB-related disorder (1)
-	-	1	Nemaline myopathy 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.87
PhyloP100		1.8
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.52
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.12		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: rs116189169; hg19: chr2-152420331;