rs762368980

Variant names:

• chr2-151546003-A-T
• rs762368980
• NM_001164507.2:c.20467-5T>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001164507.2(NEB):​c.20467-5T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000442 in 1,243,134 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: NEB NM_001164507.2 splice_region, intron
• Scores: Splicing: ADA: 0.0008130
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.940
• 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: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-151546003-A-T is Benign according to our data. Variant chr2-151546003-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 465540.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.20467-5T>A		splice_region intron	N/A	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.20467-5T>A		splice_region intron	N/A	NP_001157980.2
	NEB	NM_001271208.2		c.20467-5T>A		splice_region intron	N/A	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.20467-5T>A		splice_region intron	N/A	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.20467-5T>A		splice_region intron	N/A	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.15364-5T>A		splice_region intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00000708 AC: 1 AN: 141244 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00368 AC: 379 AN: 103110 AF XY: 0.00338

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.00456

Gnomad ASJ exome AF: 0.00311

Gnomad EAS exome AF: 0.00383

Gnomad FIN exome AF: 0.00160

Gnomad NFE exome AF: 0.00406

Gnomad OTH exome AF: 0.00387

GnomAD4 exome AF: 0.000498 AC: 549 AN: 1101890 Hom.: 0 Cov.: 19 AF XY: 0.000528 AC XY: 291 AN XY: 551290

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

African (AFR) AF: 0.0000463 AC: 1 AN: 21576

American (AMR) AF: 0.000572 AC: 18 AN: 31472

Ashkenazi Jewish (ASJ) AF: 0.000692 AC: 14 AN: 20232

East Asian (EAS) AF: 0.00 AC: 0 AN: 33338

South Asian (SAS) AF: 0.000213 AC: 13 AN: 61076

European-Finnish (FIN) AF: 0.000151 AC: 6 AN: 39646

Middle Eastern (MID) AF: 0.000433 AC: 2 AN: 4620

European-Non Finnish (NFE) AF: 0.000568 AC: 479 AN: 843894

Other (OTH) AF: 0.000348 AC: 16 AN: 46036

⚠️ 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: 0.00000708 AC: 1 AN: 141244 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 68964

African (AFR) AF: 0.00 AC: 0 AN: 34010

American (AMR) AF: 0.00 AC: 0 AN: 14636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3382

East Asian (EAS) AF: 0.00 AC: 0 AN: 5072

South Asian (SAS) AF: 0.00 AC: 0 AN: 4520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66466

Other (OTH) AF: 0.00 AC: 0 AN: 1924

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.0
DANN	Benign	0.36
PhyloP100		0.94
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00081
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.090		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: rs762368980; hg19: chr2-152402517;