chr2-151499371-A-T

Variant names:

• chr2-151499371-A-T
• rs200269437
• NM_001164507.2:c.24041T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164507.2(NEB):​c.24041T>A​(p.Val8014Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000719 in 1,391,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V8014I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.67
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2459319).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.24041T>A	p.Val8014Asp	missense	Exon 169 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.24041T>A	p.Val8014Asp	missense	Exon 169 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.24146T>A	p.Val8049Asp	missense	Exon 170 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.24041T>A	p.Val8014Asp	missense	Exon 169 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.24041T>A	p.Val8014Asp	missense	Exon 169 of 182	ENSP00000416578.2
	NEB	ENST00000688578.1		c.824T>A	p.Val275Asp	missense	Exon 10 of 21	ENSP00000509628.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000643 AC: 1 AN: 155472 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000928

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391742 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 686864

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31388

American (AMR) AF: 0.00 AC: 0 AN: 35490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25088

East Asian (EAS) AF: 0.0000282 AC: 1 AN: 35468

South Asian (SAS) AF: 0.00 AC: 0 AN: 78962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1073462

Other (OTH) AF: 0.00 AC: 0 AN: 57758

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.027	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.2	T
PhyloP100		3.7
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.13
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0020	D
Vest4		0.47
MutPred		0.54		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.42
MPC		0.079
ClinPred		0.30	T
GERP RS		6.1
gMVP		0.061
Mutation Taster		=84/16	polymorphism

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: rs200269437; hg19: chr2-152355885;