rs2288195

Variant names:

• chr2-151492512-G-A
• rs2288195
• NM_001164507.2:c.24766-18C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164508.2(NEB):​c.24766-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 1,564,944 control chromosomes in the GnomAD database, including 347,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.65 (32323 hom., cov: 28)
  • Exomes 𝑓: 0.67 (315478 hom.)
• Consequence: NEB NM_001164508.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0570
• Publications: 13 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

Specifications for NEB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-151492512-G-A is Benign according to our data. Variant chr2-151492512-G-A is described in ClinVar as Benign. ClinVar VariationId is 95122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.753 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.24766-18C>T		intron	N/A	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.24766-18C>T		intron	N/A	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.24871-18C>T		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.24766-18C>T		intron	N/A	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.24766-18C>T		intron	N/A	ENSP00000416578.2	P20929-3
	RIF1	ENST00000457745.1	TSL:1	n.481-2717G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98392 AN: 151604 Hom.: 32279 Cov.: 28

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.631

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.691

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.663

GnomAD2 exomes AF: 0.668 AC: 163483 AN: 244902 AF XY: 0.660

Gnomad AFR exome AF: 0.583

Gnomad AMR exome AF: 0.762

Gnomad ASJ exome AF: 0.640

Gnomad EAS exome AF: 0.775

Gnomad FIN exome AF: 0.687

Gnomad NFE exome AF: 0.664

Gnomad OTH exome AF: 0.675

GnomAD4 exome AF: 0.667 AC: 941975 AN: 1413222 Hom.: 315478 Cov.: 23 AF XY: 0.662 AC XY: 467378 AN XY: 705816

African (AFR) AF: 0.590 AC: 19010 AN: 32246

American (AMR) AF: 0.754 AC: 33148 AN: 43970

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 16268 AN: 25584

East Asian (EAS) AF: 0.797 AC: 31438 AN: 39454

South Asian (SAS) AF: 0.552 AC: 46719 AN: 84650

European-Finnish (FIN) AF: 0.688 AC: 36030 AN: 52380

Middle Eastern (MID) AF: 0.671 AC: 3616 AN: 5390

European-Non Finnish (NFE) AF: 0.669 AC: 716512 AN: 1070818

Other (OTH) AF: 0.668 AC: 39234 AN: 58730

GnomAD4 genome AF: 0.649 AC: 98500 AN: 151722 Hom.: 32323 Cov.: 28 AF XY: 0.653 AC XY: 48368 AN XY: 74120

African (AFR) AF: 0.582 AC: 24060 AN: 41308

American (AMR) AF: 0.727 AC: 11084 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.631 AC: 2190 AN: 3472

East Asian (EAS) AF: 0.773 AC: 3969 AN: 5134

South Asian (SAS) AF: 0.551 AC: 2631 AN: 4776

European-Finnish (FIN) AF: 0.691 AC: 7277 AN: 10530

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45135 AN: 67948

Other (OTH) AF: 0.667 AC: 1404 AN: 2106

Alfa AF: 0.659 Hom.: 11533

Bravo AF: 0.654

Asia WGS AF: 0.652 AC: 2269 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Nemaline myopathy 2 (2)
-	-	2	not provided (2)
-	-	1	Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.54
DANN	Benign	0.67
PhyloP100		-0.057
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2288195;

hg19: chr2-152349026;

COSMIC: COSV51437773;

COSMIC: COSV51437773;