2-151560958-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001164507.2(NEB):c.19206+46C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,176,964 control chromosomes in the GnomAD database, including 325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (61 hom., cov: 32)
  • Exomes 𝑓: 0.021 (264 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.411

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-151560958-G-T is Benign according to our data. Variant chr2-151560958-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 257778.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151560958-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0248 (3765/151758) while in subpopulation AFR AF= 0.0379 (1569/41384). AF 95% confidence interval is 0.0364. There are 61 homozygotes in gnomad4. There are 1859 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 61 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.19206+46C>A		intron_variant		ENST00000427231.7
NEB	NM_001164508.2	c.19206+46C>A		intron_variant		ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.19206+46C>A		intron_variant		5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.19206+46C>A		intron_variant		5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3754 AN: 151640 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0377

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00522

Gnomad FIN AF: 0.0407

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0206

Gnomad OTH AF: 0.0241

GnomAD3 exomes AF: 0.0193 AC: 3631 AN: 188430 Hom.: 49 AF XY: 0.0187 AC XY: 1873 AN XY: 100198

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.00892

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00618

Gnomad FIN exome AF: 0.0355

Gnomad NFE exome AF: 0.0224

Gnomad OTH exome AF: 0.0221

GnomAD4 exome AF: 0.0209 AC: 21430 AN: 1025206 Hom.: 264 Cov.: 13 AF XY: 0.0201 AC XY: 10519 AN XY: 523408

Gnomad4 AFR exome AF: 0.0375

Gnomad4 AMR exome AF: 0.00997

Gnomad4 ASJ exome AF: 0.0231

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.00688

Gnomad4 FIN exome AF: 0.0350

Gnomad4 NFE exome AF: 0.0222

Gnomad4 OTH exome AF: 0.0205

GnomAD4 genome AF: 0.0248 AC: 3765 AN: 151758 Hom.: 61 Cov.: 32 AF XY: 0.0251 AC XY: 1859 AN XY: 74194

Gnomad4 AFR AF: 0.0379

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00523

Gnomad4 FIN AF: 0.0407

Gnomad4 NFE AF: 0.0206

Gnomad4 OTH AF: 0.0238

Alfa AF: 0.0231 Hom.: 11

Bravo AF: 0.0236

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	-0.86
Cadd	Benign	0.84
Dann	Benign	0.49

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: rs76261031; hg19: chr2-152417472;