rs150471104

chr2-151514449-A-G

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.23017-21T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00783 in 1,534,584 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (66 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.51

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]

RIF1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 2-151514449-A-G is Benign according to our data. Variant chr2-151514449-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 257794.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151514449-A-G is described in Lovd as [Benign]. Variant chr2-151514449-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00668 (1017/152328) while in subpopulation NFE AF= 0.00932 (634/68028). AF 95% confidence interval is 0.00872. There are 6 homozygotes in gnomad4. There are 536 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.23017-21T>C		intron_variant		ENST00000427231.7
NEB	NM_001164508.2	c.23017-21T>C		intron_variant		ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.23017-21T>C		intron_variant		5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.23017-21T>C		intron_variant		5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.00668 AC: 1017 AN: 152210 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00932

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00682 AC: 1694 AN: 248540 Hom.: 13 AF XY: 0.00734 AC XY: 989 AN XY: 134804

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.00479

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00775

Gnomad FIN exome AF: 0.0139

Gnomad NFE exome AF: 0.00799

Gnomad OTH exome AF: 0.00530

GnomAD4 exome AF: 0.00796 AC: 11002 AN: 1382256 Hom.: 66 Cov.: 23 AF XY: 0.00798 AC XY: 5523 AN XY: 692512

Gnomad4 AFR exome AF: 0.00154

Gnomad4 AMR exome AF: 0.00484

Gnomad4 ASJ exome AF: 0.00354

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00707

Gnomad4 FIN exome AF: 0.0132

Gnomad4 NFE exome AF: 0.00863

Gnomad4 OTH exome AF: 0.00608

GnomAD4 genome AF: 0.00668 AC: 1017 AN: 152328 Hom.: 6 Cov.: 32 AF XY: 0.00720 AC XY: 536 AN XY: 74486

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.00791

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0127

Gnomad4 NFE AF: 0.00932

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00731 Hom.: 0

Bravo AF: 0.00529

Asia WGS AF: 0.00202 AC: 7 AN: 3478

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	-0.76
Cadd	Benign	12
Dann	Benign	0.68

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: rs150471104; hg19: chr2-152370963;