chr2-151534292-G-A

Variant names:

• chr2-151534292-G-A
• rs186686151
• NM_001164507.2:c.21340C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001164507.2(NEB):​c.21340C>T​(p.Arg7114Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,613,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7114Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 2.23
• Publications: 1 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-151534292-G-A is Benign according to our data. Variant chr2-151534292-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 557244.

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.21340C>T	p.Arg7114Trp	missense	Exon 143 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.21313-746C>T		intron	N/A	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.21340C>T	p.Arg7114Trp	missense	Exon 143 of 183	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.21340C>T	p.Arg7114Trp	missense	Exon 143 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.21313-746C>T		intron	N/A	ENSP00000380505.3	P20929-2
	NEB	ENST00000409198.5	TSL:5	c.16237C>T	p.Arg5413Trp	missense	Exon 116 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000137 AC: 34 AN: 248486 AF XY: 0.000111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00173

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000424 AC: 62 AN: 1461166 Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26 AN XY: 726926

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00111 AC: 44 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111712

Other (OTH) AF: 0.0000663 AC: 4 AN: 60362

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74444

African (AFR) AF: 0.0000481 AC: 2 AN: 41538

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000249 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.000116 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	Nemaline myopathy 2 (4)
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.29
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.61
MVP		0.64
ClinPred		0.13	T
GERP RS		5.9
Varity_R		0.16
gMVP		0.14
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.36		Position offset: 27

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs186686151; hg19: chr2-152390806;