rs2288193

Variant names:

• chr2-151492328-T-A
• rs2288193
• NM_001164507.2:c.24874-47A>T

Variant summary

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

The NM_001164507.2(NEB):​c.24874-47A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,593,840 control chromosomes in the GnomAD database, including 89,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6203 hom., cov: 31)
  • Exomes 𝑓: 0.33 (83752 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.887
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-151492328-T-A is Benign according to our data. Variant chr2-151492328-T-A is described in ClinVar as Benign. ClinVar VariationId is 257804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.24874-47A>T		intron_variant	Intron 177 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.24874-47A>T		intron_variant	Intron 177 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.24874-47A>T		intron_variant	Intron 177 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.24874-47A>T		intron_variant	Intron 177 of 181	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39680 AN: 151960 Hom.: 6197 Cov.: 31

Gnomad AFR AF: 0.0820

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.269

GnomAD2 exomes AF: 0.301 AC: 71191 AN: 236906 AF XY: 0.299

Gnomad AFR exome AF: 0.0748

Gnomad AMR exome AF: 0.322

Gnomad ASJ exome AF: 0.249

Gnomad EAS exome AF: 0.262

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.350

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.335 AC: 482412 AN: 1441762 Hom.: 83752 Cov.: 30 AF XY: 0.330 AC XY: 236330 AN XY: 715206

African (AFR) AF: 0.0712 AC: 2344 AN: 32914

American (AMR) AF: 0.316 AC: 13645 AN: 43222

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6139 AN: 24964

East Asian (EAS) AF: 0.279 AC: 11023 AN: 39476

South Asian (SAS) AF: 0.202 AC: 16892 AN: 83758

European-Finnish (FIN) AF: 0.350 AC: 18461 AN: 52684

Middle Eastern (MID) AF: 0.290 AC: 1639 AN: 5646

European-Non Finnish (NFE) AF: 0.358 AC: 394053 AN: 1099636

Other (OTH) AF: 0.306 AC: 18216 AN: 59462

GnomAD4 genome AF: 0.261 AC: 39690 AN: 152078 Hom.: 6203 Cov.: 31 AF XY: 0.261 AC XY: 19380 AN XY: 74324

African (AFR) AF: 0.0819 AC: 3400 AN: 41516

American (AMR) AF: 0.287 AC: 4380 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 827 AN: 3470

East Asian (EAS) AF: 0.257 AC: 1328 AN: 5174

South Asian (SAS) AF: 0.202 AC: 975 AN: 4816

European-Finnish (FIN) AF: 0.360 AC: 3798 AN: 10552

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.356 AC: 24205 AN: 67982

Other (OTH) AF: 0.266 AC: 561 AN: 2108

Alfa AF: 0.304 Hom.: 1366

Bravo AF: 0.248

Asia WGS AF: 0.228 AC: 793 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nemaline myopathy 2 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis multiplex congenita 6 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.3
DANN	Benign	0.56
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2288193; hg19: chr2-152348842; COSMIC: COSV50868309; COSMIC: COSV50868309;