chr2-151499371-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001164508.2(NEB):​c.24041T>C​(p.Val8014Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000254 in 1,543,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict 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. V8014I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11454207).
• BP6: Variant 2-151499371-A-G is Benign according to our data. Variant chr2-151499371-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 506584.

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.24041T>C	p.Val8014Ala	missense	Exon 169 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.24041T>C	p.Val8014Ala	missense	Exon 169 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.24146T>C	p.Val8049Ala	missense	Exon 170 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.24041T>C	p.Val8014Ala	missense	Exon 169 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.24041T>C	p.Val8014Ala	missense	Exon 169 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000688578.1		c.824T>C	p.Val275Ala	missense	Exon 10 of 21	ENSP00000509628.1	A0A8I5KS37

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000154 AC: 24 AN: 155472 AF XY: 0.000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000369

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000182

Gnomad OTH exome AF: 0.000686

GnomAD4 exome AF: 0.000264 AC: 367 AN: 1391726 Hom.: 0 Cov.: 26 AF XY: 0.000274 AC XY: 188 AN XY: 686854

African (AFR) AF: 0.0000956 AC: 3 AN: 31388

American (AMR) AF: 0.000451 AC: 16 AN: 35490

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25088

East Asian (EAS) AF: 0.0000846 AC: 3 AN: 35468

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78962

European-Finnish (FIN) AF: 0.0000206 AC: 1 AN: 48452

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5674

European-Non Finnish (NFE) AF: 0.000307 AC: 330 AN: 1073446

Other (OTH) AF: 0.000190 AC: 11 AN: 57758

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74330

African (AFR) AF: 0.000121 AC: 5 AN: 41440

American (AMR) AF: 0.000131 AC: 2 AN: 15262

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

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000298 Hom.: 1

Bravo AF: 0.000181

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000568 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Nemaline myopathy 2 (2)
-	1	1	not provided (2)
-	1	-	NEB-related disorder (1)
-	1	-	Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.0056
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.88	T
PhyloP100		3.7
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.10
Sift	Benign	0.15	T
Sift4G	Benign	0.11	T
Vest4		0.28
MVP		0.50
MPC		0.059
ClinPred		0.060	T
GERP RS		6.1
gMVP		0.023
Mutation Taster		=93/7	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; COSMIC: COSV105041739; COSMIC: COSV105041739;