rs113048349

Variant names:

• chr2-151497725-G-A
• rs113048349
• NM_001164507.2:c.24208-7C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-151497725-G-A
• chr2-151497725-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001271208.2(NEB):​c.24313-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,567,582 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (134 hom.)
• Consequence: NEB NM_001271208.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003053
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.516
• Publications: 4 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=-0.93).
• BP6: Variant 2-151497725-G-A is Benign according to our data. Variant chr2-151497725-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00891 (1356/152222) while in subpopulation NFE AF = 0.0121 (820/68014). AF 95% confidence interval is 0.0114. There are 7 homozygotes in GnomAd4. There are 663 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271208.2. 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.24208-7C>T		splice_region intron	N/A	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.24208-7C>T		splice_region intron	N/A	NP_001157980.2
	NEB	NM_001271208.2		c.24313-7C>T		splice_region 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.24208-7C>T		splice_region intron	N/A	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.24208-7C>T		splice_region intron	N/A	ENSP00000416578.2
	RIF1	ENST00000457745.1	TSL:1	n.579-61G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00890 AC: 1354 AN: 152104 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.0106 AC: 1899 AN: 179642 AF XY: 0.0110

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00317

Gnomad ASJ exome AF: 0.0432

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0118 AC: 16686 AN: 1415360 Hom.: 134 Cov.: 32 AF XY: 0.0118 AC XY: 8244 AN XY: 699410

African (AFR) AF: 0.00163 AC: 53 AN: 32466

American (AMR) AF: 0.00391 AC: 147 AN: 37602

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 1108 AN: 25500

East Asian (EAS) AF: 0.0000263 AC: 1 AN: 37964

South Asian (SAS) AF: 0.0108 AC: 867 AN: 80018

European-Finnish (FIN) AF: 0.0112 AC: 567 AN: 50822

Middle Eastern (MID) AF: 0.0126 AC: 72 AN: 5710

European-Non Finnish (NFE) AF: 0.0120 AC: 13019 AN: 1086578

Other (OTH) AF: 0.0145 AC: 852 AN: 58700

GnomAD4 genome AF: 0.00891 AC: 1356 AN: 152222 Hom.: 7 Cov.: 32 AF XY: 0.00891 AC XY: 663 AN XY: 74430

African (AFR) AF: 0.00248 AC: 103 AN: 41534

American (AMR) AF: 0.00654 AC: 100 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0386 AC: 134 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00892 AC: 43 AN: 4820

European-Finnish (FIN) AF: 0.0116 AC: 123 AN: 10590

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 820 AN: 68014

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.00933 Hom.: 3

Bravo AF: 0.00812

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Nemaline myopathy 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.41
DANN	Benign	0.58
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0020
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: rs113048349; hg19: chr2-152354239;