rs4414676

Variant names:

• chr2-151491671-C-T
• rs4414676
• NM_001164507.2:c.25150+12G>A

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.25150+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,565,382 control chromosomes in the GnomAD database, including 2,221 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 0.067 (1119 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (1102 hom.)
• Consequence: NEB NM_001164508.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.01
• Publications: 5 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=-0.71).
• BP6: Variant 2-151491671-C-T is Benign according to our data. Variant chr2-151491671-C-T is described in ClinVar as Benign. ClinVar VariationId is 226845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 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.25150+12G>A		intron	N/A	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.25150+12G>A		intron	N/A	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.25255+12G>A		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.25150+12G>A		intron	N/A	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.25150+12G>A		intron	N/A	ENSP00000416578.2	P20929-3
	RIF1	ENST00000457745.1	TSL:1	n.481-3558C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0672 AC: 10216 AN: 152098 Hom.: 1118 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0302

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.0592

GnomAD2 exomes AF: 0.0163 AC: 3208 AN: 196570 AF XY: 0.0124

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000664

Gnomad OTH exome AF: 0.00893

GnomAD4 exome AF: 0.00719 AC: 10159 AN: 1413166 Hom.: 1102 Cov.: 29 AF XY: 0.00624 AC XY: 4367 AN XY: 699792

African (AFR) AF: 0.246 AC: 7965 AN: 32422

American (AMR) AF: 0.0130 AC: 509 AN: 39196

Ashkenazi Jewish (ASJ) AF: 0.0000788 AC: 2 AN: 25370

East Asian (EAS) AF: 0.00 AC: 0 AN: 38050

South Asian (SAS) AF: 0.000632 AC: 51 AN: 80636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51336

Middle Eastern (MID) AF: 0.0211 AC: 120 AN: 5700

European-Non Finnish (NFE) AF: 0.000454 AC: 491 AN: 1081652

Other (OTH) AF: 0.0174 AC: 1021 AN: 58804

GnomAD4 genome AF: 0.0672 AC: 10231 AN: 152216 Hom.: 1119 Cov.: 32 AF XY: 0.0641 AC XY: 4771 AN XY: 74430

African (AFR) AF: 0.231 AC: 9581 AN: 41484

American (AMR) AF: 0.0302 AC: 462 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68026

Other (OTH) AF: 0.0591 AC: 125 AN: 2116

Alfa AF: 0.0447 Hom.: 168

Bravo AF: 0.0784

Asia WGS AF: 0.0140 AC: 51 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Nemaline myopathy 2 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.9
DANN	Benign	0.82
PhyloP100		-1.0
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: rs4414676; hg19: chr2-152348185;