rs374484102

chr2-151538025-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001164507.2(NEB):c.20998-49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000806 in 1,542,574 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (1 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00900

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]

LOC124906081 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-151538025-G-A is Benign according to our data. Variant chr2-151538025-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257787.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.20998-49C>T		intron_variant		ENST00000427231.7
NEB	NM_001164508.2	c.20998-49C>T		intron_variant		ENST00000397345.8
LOC124906081	XR_007087266.1	n.250G>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.20998-49C>T		intron_variant		5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.20998-49C>T		intron_variant		5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 76 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000407 AC: 98 AN: 241068 Hom.: 0 AF XY: 0.000436 AC XY: 57 AN XY: 130708

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000377

Gnomad NFE exome AF: 0.000770

Gnomad OTH exome AF: 0.000344

GnomAD4 exome AF: 0.000840 AC: 1168 AN: 1390306 Hom.: 1 Cov.: 22 AF XY: 0.000816 AC XY: 567 AN XY: 694706

Gnomad4 AFR exome AF: 0.000126

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000414

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.00145

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74442

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000513 Hom.: 0

Bravo AF: 0.000536

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.78
Dann	Benign	0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs374484102; hg19: chr2-152394539;