rs16830128

Variant names:

• chr2-151513538-A-G
• rs16830128
• NM_001164507.2:c.23241+42T>C

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.23241+42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,424,300 control chromosomes in the GnomAD database, including 766 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 0.015 (79 hom., cov: 32)
  • Exomes 𝑓: 0.011 (687 hom.)
• Consequence: NEB NM_001164508.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0610
• 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

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=-0.86).
• BP6: Variant 2-151513538-A-G is Benign according to our data. Variant chr2-151513538-A-G is described in ClinVar as Benign. ClinVar VariationId is 257798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 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.23241+42T>C		intron	N/A	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.23241+42T>C		intron	N/A	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.23346+42T>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.23241+42T>C		intron	N/A	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.23241+42T>C		intron	N/A	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.18138+42T>C		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2227 AN: 152170 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.0755

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00195

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0233 AC: 4180 AN: 179392 AF XY: 0.0259

Gnomad AFR exome AF: 0.0179

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.0315

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.0000559

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.0111 AC: 14144 AN: 1272012 Hom.: 687 Cov.: 17 AF XY: 0.0129 AC XY: 8209 AN XY: 635660

African (AFR) AF: 0.0169 AC: 498 AN: 29450

American (AMR) AF: 0.00289 AC: 105 AN: 36378

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 755 AN: 24246

East Asian (EAS) AF: 0.136 AC: 5061 AN: 37140

South Asian (SAS) AF: 0.0679 AC: 5208 AN: 76680

European-Finnish (FIN) AF: 0.000277 AC: 14 AN: 50538

Middle Eastern (MID) AF: 0.0128 AC: 69 AN: 5400

European-Non Finnish (NFE) AF: 0.00147 AC: 1405 AN: 958326

Other (OTH) AF: 0.0191 AC: 1029 AN: 53854

GnomAD4 genome AF: 0.0148 AC: 2261 AN: 152288 Hom.: 79 Cov.: 32 AF XY: 0.0162 AC XY: 1204 AN XY: 74472

African (AFR) AF: 0.0175 AC: 729 AN: 41560

American (AMR) AF: 0.00752 AC: 115 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3468

East Asian (EAS) AF: 0.142 AC: 732 AN: 5168

South Asian (SAS) AF: 0.0764 AC: 369 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00196 AC: 133 AN: 68028

Other (OTH) AF: 0.0336 AC: 71 AN: 2112

Alfa AF: 0.00774 Hom.: 11

Bravo AF: 0.0140

Asia WGS AF: 0.124 AC: 428 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.8
DANN	Benign	0.63
PhyloP100		-0.061
PromoterAI		-0.0042	Neutral
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: rs16830128; hg19: chr2-152370052; COSMIC: COSV51419678; COSMIC: COSV51419678;