NM_001164507.2:c.25204A>G

Variant names:

• chr2-151490465-T-C
• rs1061305
• NM_001164507.2:c.25204A>G

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.25204A>G​(p.Ile8402Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,606,238 control chromosomes in the GnomAD database, including 132,868 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.40 (12178 hom., cov: 31)
  • Exomes 𝑓: 0.40 (120690 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.715
• Publications: 30 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 (MetaRNN=3.4809113E-4).
• BP6: Variant 2-151490465-T-C is Benign according to our data. Variant chr2-151490465-T-C is described in ClinVar as Benign. ClinVar VariationId is 95126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. 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.25204A>G	p.Ile8402Val	missense	Exon 180 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.25204A>G	p.Ile8402Val	missense	Exon 180 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.25309A>G	p.Ile8437Val	missense	Exon 181 of 183	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.25204A>G	p.Ile8402Val	missense	Exon 180 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.25204A>G	p.Ile8402Val	missense	Exon 180 of 182	ENSP00000416578.2	P20929-3
	RIF1	ENST00000457745.1	TSL:1	n.480+3709T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60407 AN: 151876 Hom.: 12161 Cov.: 31

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.386

GnomAD2 exomes AF: 0.366 AC: 87104 AN: 237766 AF XY: 0.359

Gnomad AFR exome AF: 0.437

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.295

Gnomad EAS exome AF: 0.263

Gnomad FIN exome AF: 0.379

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.402 AC: 585038 AN: 1454244 Hom.: 120690 Cov.: 47 AF XY: 0.396 AC XY: 286115 AN XY: 722416

African (AFR) AF: 0.440 AC: 14664 AN: 33350

American (AMR) AF: 0.362 AC: 15893 AN: 43928

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 7600 AN: 25920

East Asian (EAS) AF: 0.280 AC: 11046 AN: 39444

South Asian (SAS) AF: 0.227 AC: 19193 AN: 84574

European-Finnish (FIN) AF: 0.383 AC: 20298 AN: 52954

Middle Eastern (MID) AF: 0.352 AC: 2024 AN: 5756

European-Non Finnish (NFE) AF: 0.426 AC: 471635 AN: 1108212

Other (OTH) AF: 0.377 AC: 22685 AN: 60106

GnomAD4 genome AF: 0.398 AC: 60463 AN: 151994 Hom.: 12178 Cov.: 31 AF XY: 0.391 AC XY: 29069 AN XY: 74304

African (AFR) AF: 0.433 AC: 17939 AN: 41462

American (AMR) AF: 0.356 AC: 5445 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 999 AN: 3470

East Asian (EAS) AF: 0.259 AC: 1335 AN: 5162

South Asian (SAS) AF: 0.225 AC: 1084 AN: 4824

European-Finnish (FIN) AF: 0.388 AC: 4093 AN: 10550

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.419 AC: 28437 AN: 67940

Other (OTH) AF: 0.382 AC: 804 AN: 2106

Alfa AF: 0.406 Hom.: 58355

Bravo AF: 0.401

TwinsUK AF: 0.430 AC: 1594

ALSPAC AF: 0.422 AC: 1627

ESP6500AA AF: 0.427 AC: 1744

ESP6500EA AF: 0.415 AC: 3495

ExAC AF: 0.364 AC: 43955

Asia WGS AF: 0.261 AC: 909 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Nemaline myopathy 2 (4)
-	-	2	not provided (2)
-	-	1	Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.7
DANN	Benign	0.94
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.00035	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.71
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.053
Sift	Benign	0.38	T
Sift4G	Benign	0.14	T
Polyphen		0.0010	B
Vest4		0.051
MPC		0.046
ClinPred		0.0015	T
GERP RS		0.40
Varity_R		0.052
gMVP		0.26
Mutation Taster		=98/2	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: rs1061305; hg19: chr2-152346979; COSMIC: COSV51445294; COSMIC: COSV51445294;