rs765107380

Variant names:

• chr2-151545999-C-CT
• rs765107380
• NM_001164507.2:c.20467-2dupA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PVS1_Moderate BP6_Moderate BS1

The NM_001164508.2(NEB):​c.20467-2dupA variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 832,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: NEB NM_001164508.2 splice_acceptor, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 3.30
• 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

LOC124906081 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.004339667 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8, offset of 0 (no position change), new splice context is: ttttttttttttttttaaAGtct. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 2-151545999-C-CT is Benign according to our data. Variant chr2-151545999-C-CT is described in ClinVar as Likely_benign. ClinVar VariationId is 465538.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000296 (27/91244) while in subpopulation EAS AF = 0.00452 (14/3094). AF 95% confidence interval is 0.00274. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 27. 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.20467-2dupA		splice_acceptor intron	N/A	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.20467-2dupA		splice_acceptor intron	N/A	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.20467-2dupA		splice_acceptor 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.20467-2_20467-1insA		splice_acceptor intron	N/A	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.20467-2_20467-1insA		splice_acceptor intron	N/A	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.15364-2_15364-1insA		splice_acceptor intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 27 AN: 91180 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00451

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000269

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000497

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000972 AC: 100 AN: 102918 AF XY: 0.000891

Gnomad AFR exome AF: 0.000560

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.000753

Gnomad EAS exome AF: 0.00383

Gnomad FIN exome AF: 0.000502

Gnomad NFE exome AF: 0.000798

Gnomad OTH exome AF: 0.00144

GnomAD4 exome AF: 0.00131 AC: 972 AN: 741628 Hom.: 0 Cov.: 19 AF XY: 0.00127 AC XY: 490 AN XY: 384344

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000407 AC: 8 AN: 19666

American (AMR) AF: 0.000860 AC: 21 AN: 24428

Ashkenazi Jewish (ASJ) AF: 0.000983 AC: 19 AN: 19328

East Asian (EAS) AF: 0.00157 AC: 47 AN: 29910

South Asian (SAS) AF: 0.000409 AC: 25 AN: 61174

European-Finnish (FIN) AF: 0.000261 AC: 9 AN: 34434

Middle Eastern (MID) AF: 0.00257 AC: 10 AN: 3884

European-Non Finnish (NFE) AF: 0.00149 AC: 765 AN: 513690

Other (OTH) AF: 0.00194 AC: 68 AN: 35114

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000296 AC: 27 AN: 91244 Hom.: 0 Cov.: 27 AF XY: 0.000233 AC XY: 10 AN XY: 42946

African (AFR) AF: 0.000340 AC: 10 AN: 29416

American (AMR) AF: 0.00 AC: 0 AN: 6974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2566

East Asian (EAS) AF: 0.00452 AC: 14 AN: 3094

South Asian (SAS) AF: 0.00 AC: 0 AN: 3108

European-Finnish (FIN) AF: 0.000269 AC: 1 AN: 3722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 158

European-Non Finnish (NFE) AF: 0.0000497 AC: 2 AN: 40278

Other (OTH) AF: 0.00 AC: 0 AN: 1226

Alfa AF: 0.000420 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	NEB-related disorder (1)
-	-	1	Nemaline myopathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs765107380; hg19: chr2-152402513; COSMIC: COSV51460554;