2-151499847-A-G

Variant names:

• chr2-151499847-A-G
• rs9287979
• NM_001164507.2:c.24022-457T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001164508.2(NEB):​c.24022-457T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.593 in 152,016 control chromosomes in the GnomAD database, including 27,141 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.59 (27141 hom., cov: 32)
• Consequence: NEB NM_001164508.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.131
• Publications: 2 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]

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164508.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.24022-457T>C		intron	N/A	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.24022-457T>C		intron	N/A	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.24127-457T>C		intron	N/A	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.24022-457T>C		intron	N/A	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.24022-457T>C		intron	N/A	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.18825+2946T>C		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.593 AC: 90086 AN: 151898 Hom.: 27114 Cov.: 32

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.697

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.643

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.591

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.593 AC: 90155 AN: 152016 Hom.: 27141 Cov.: 32 AF XY: 0.594 AC XY: 44122 AN XY: 74290

African (AFR) AF: 0.520 AC: 21549 AN: 41480

American (AMR) AF: 0.698 AC: 10652 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1772 AN: 3468

East Asian (EAS) AF: 0.583 AC: 3012 AN: 5166

South Asian (SAS) AF: 0.405 AC: 1953 AN: 4818

European-Finnish (FIN) AF: 0.643 AC: 6780 AN: 10540

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.626 AC: 42545 AN: 67958

Other (OTH) AF: 0.584 AC: 1233 AN: 2110

Alfa AF: 0.536 Hom.: 1782

Bravo AF: 0.599

Asia WGS AF: 0.465 AC: 1618 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.5
DANN	Benign	0.68
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9287979; hg19: chr2-152356361;