2-151563606-C-G

Variant names:

• chr2-151563606-C-G
• rs141338915
• NM_001164507.2:c.18693G>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_004543.5(NEB):​c.13590G>C​(p.Ala4530Ala) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,611,602 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (11 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (38 hom.)
• Consequence: NEB NM_004543.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9982
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 7.63
• 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 2-151563606-C-G is Benign according to our data. Variant chr2-151563606-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00481 (733/152292) while in subpopulation EAS AF = 0.0454 (235/5178). AF 95% confidence interval is 0.0406. There are 11 homozygotes in GnomAd4. There are 379 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004543.5. 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.18693G>C	p.Ala6231Ala	synonymous	Exon 119 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.18693G>C	p.Ala6231Ala	synonymous	Exon 119 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.18693G>C	p.Ala6231Ala	synonymous	Exon 119 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.18693G>C	p.Ala6231Ala	synonymous	Exon 119 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.18693G>C	p.Ala6231Ala	synonymous	Exon 119 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.13590G>C	p.Ala4530Ala	splice_region synonymous	Exon 92 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00480 AC: 730 AN: 152174 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00910

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0461

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00619 AC: 1541 AN: 248958 AF XY: 0.00578

Gnomad AFR exome AF: 0.00846

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0494

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000222

Gnomad OTH exome AF: 0.00331

GnomAD4 exome AF: 0.00186 AC: 2720 AN: 1459310 Hom.: 38 Cov.: 30 AF XY: 0.00183 AC XY: 1332 AN XY: 726140

African (AFR) AF: 0.00907 AC: 303 AN: 33398

American (AMR) AF: 0.00997 AC: 446 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.0314 AC: 1245 AN: 39692

South Asian (SAS) AF: 0.00365 AC: 315 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5760

European-Non Finnish (NFE) AF: 0.0000982 AC: 109 AN: 1109708

Other (OTH) AF: 0.00484 AC: 292 AN: 60300

GnomAD4 genome AF: 0.00481 AC: 733 AN: 152292 Hom.: 11 Cov.: 31 AF XY: 0.00509 AC XY: 379 AN XY: 74446

African (AFR) AF: 0.00924 AC: 384 AN: 41552

American (AMR) AF: 0.00490 AC: 75 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0454 AC: 235 AN: 5178

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68034

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00163 Hom.: 2

Bravo AF: 0.00589

Asia WGS AF: 0.0170 AC: 58 AN: 3476

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	3	Nemaline myopathy 2 (3)
-	-	1	Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Benign	0.82
PhyloP100		7.6
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.15		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: rs141338915; hg19: chr2-152420120; COSMIC: COSV107248050;