rs145127681

Variant names:

• chr2-151561114-G-A
• rs145127681
• NM_001164507.2:c.19102-6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164508.2(NEB):​c.19102-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 1,568,874 control chromosomes in the GnomAD database, including 1,322 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (120 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1202 hom.)
• Consequence: NEB NM_001164508.2 splice_region, intron
• Scores: Splicing: ADA: 0.00001807
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0410
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-151561114-G-A is Benign according to our data. Variant chr2-151561114-G-A is described in ClinVar as Benign. ClinVar VariationId is 129717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0286 (4355/152202) while in subpopulation NFE AF = 0.0412 (2800/68006). AF 95% confidence interval is 0.0399. There are 120 homozygotes in GnomAd4. There are 2265 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 120 AD,AR gene

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.19102-6C>T		splice_region intron	N/A	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.19102-6C>T		splice_region intron	N/A	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.19102-6C>T		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.19102-6C>T		splice_region intron	N/A	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.19102-6C>T		splice_region intron	N/A	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.13999-6C>T		splice_region intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4354 AN: 152084 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.00565

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0976

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0412

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0274 AC: 6398 AN: 233910 AF XY: 0.0279

Gnomad AFR exome AF: 0.00480

Gnomad AMR exome AF: 0.00785

Gnomad ASJ exome AF: 0.00692

Gnomad EAS exome AF: 0.000117

Gnomad FIN exome AF: 0.0929

Gnomad NFE exome AF: 0.0361

Gnomad OTH exome AF: 0.0240

GnomAD4 exome AF: 0.0364 AC: 51578 AN: 1416672 Hom.: 1202 Cov.: 25 AF XY: 0.0355 AC XY: 25026 AN XY: 705314

African (AFR) AF: 0.00451 AC: 145 AN: 32124

American (AMR) AF: 0.00834 AC: 355 AN: 42560

Ashkenazi Jewish (ASJ) AF: 0.00714 AC: 181 AN: 25358

East Asian (EAS) AF: 0.00 AC: 0 AN: 39326

South Asian (SAS) AF: 0.00358 AC: 296 AN: 82704

European-Finnish (FIN) AF: 0.0853 AC: 4495 AN: 52686

Middle Eastern (MID) AF: 0.00124 AC: 7 AN: 5626

European-Non Finnish (NFE) AF: 0.0412 AC: 44411 AN: 1077498

Other (OTH) AF: 0.0287 AC: 1688 AN: 58790

GnomAD4 genome AF: 0.0286 AC: 4355 AN: 152202 Hom.: 120 Cov.: 32 AF XY: 0.0304 AC XY: 2265 AN XY: 74414

African (AFR) AF: 0.00563 AC: 234 AN: 41540

American (AMR) AF: 0.0134 AC: 204 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00721 AC: 25 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4820

European-Finnish (FIN) AF: 0.0976 AC: 1034 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0412 AC: 2800 AN: 68006

Other (OTH) AF: 0.0170 AC: 36 AN: 2116

Alfa AF: 0.0330 Hom.: 53

Bravo AF: 0.0204

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Nemaline myopathy 2 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.8
DANN	Benign	0.39
PhyloP100		0.041
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0
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: rs145127681; hg19: chr2-152417628;