rs553020641

Positions:

• chr2-151680054-ATAAAG-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001164508.2(NEB):​c.3043-37_3043-33delCTTTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,459,110 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (8 hom.)
• Consequence: NEB NM_001164508.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.08

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 -10 ACMG points.

• BP6: Variant 2-151680054-ATAAAG-A is Benign according to our data. Variant chr2-151680054-ATAAAG-A is described in ClinVar as [Likely_benign]. Clinvar id is 257808.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00172 (2242/1306746) while in subpopulation MID AF= 0.00548 (30/5472). AF 95% confidence interval is 0.00395. There are 8 homozygotes in gnomad4_exome. There are 1146 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.3043-37_3043-33delCTTTA		intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.3043-37_3043-33delCTTTA		intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.3043-37_3043-33delCTTTA		intron_variant		5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.3043-37_3043-33delCTTTA		intron_variant		5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.3043-37_3043-33delCTTTA		intron_variant		5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152246 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.0263

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00209 AC: 493 AN: 235788 Hom.: 4 AF XY: 0.00218 AC XY: 279 AN XY: 127908

Gnomad AFR exome AF: 0.000337

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000912

Gnomad FIN exome AF: 0.0000946

Gnomad NFE exome AF: 0.00185

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00172 AC: 2242 AN: 1306746 Hom.: 8 AF XY: 0.00174 AC XY: 1146 AN XY: 656940

Gnomad4 AFR exome AF: 0.000326

Gnomad4 AMR exome AF: 0.00178

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000757

Gnomad4 FIN exome AF: 0.0000942

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.00274

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152364 Hom.: 1 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74512

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.0263

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00491 Hom.: 1

Bravo AF: 0.00176

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs553020641; hg19: chr2-152536568;