chr2-151671058-C-T

Variant names:

• chr2-151671058-C-T
• rs7426114
• NM_001164507.2:c.4471G>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.4471G>A​(p.Val1491Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 1,613,714 control chromosomes in the GnomAD database, including 519,826 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1491L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.66 (38361 hom., cov: 32)
  • Exomes 𝑓: 0.80 (481465 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 3.39
• Publications: 38 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]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen
• autosomal dominant nebulin-related myopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1006094E-6).
• BP6: Variant 2-151671058-C-T is Benign according to our data. Variant chr2-151671058-C-T is described in ClinVar as Benign. ClinVar VariationId is 95131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.836 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.4471G>A	p.Val1491Met	missense	Exon 38 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.4471G>A	p.Val1491Met	missense	Exon 38 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.4471G>A	p.Val1491Met	missense	Exon 38 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.4471G>A	p.Val1491Met	missense	Exon 38 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.4471G>A	p.Val1491Met	missense	Exon 38 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.4471G>A	p.Val1491Met	missense	Exon 38 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.665 AC: 101125 AN: 151990 Hom.: 38358 Cov.: 32

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.823

Gnomad AMR AF: 0.806

Gnomad ASJ AF: 0.739

Gnomad EAS AF: 0.393

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.868

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.841

Gnomad OTH AF: 0.701

GnomAD2 exomes AF: 0.751 AC: 187196 AN: 249228 AF XY: 0.755

Gnomad AFR exome AF: 0.277

Gnomad AMR exome AF: 0.860

Gnomad ASJ exome AF: 0.749

Gnomad EAS exome AF: 0.410

Gnomad FIN exome AF: 0.860

Gnomad NFE exome AF: 0.842

Gnomad OTH exome AF: 0.783

GnomAD4 exome AF: 0.802 AC: 1172173 AN: 1461606 Hom.: 481465 Cov.: 67 AF XY: 0.800 AC XY: 581351 AN XY: 727090

African (AFR) AF: 0.275 AC: 9193 AN: 33468

American (AMR) AF: 0.852 AC: 38087 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.748 AC: 19562 AN: 26136

East Asian (EAS) AF: 0.379 AC: 15060 AN: 39700

South Asian (SAS) AF: 0.663 AC: 57195 AN: 86256

European-Finnish (FIN) AF: 0.858 AC: 45815 AN: 53400

Middle Eastern (MID) AF: 0.770 AC: 4444 AN: 5768

European-Non Finnish (NFE) AF: 0.843 AC: 937195 AN: 1111790

Other (OTH) AF: 0.756 AC: 45622 AN: 60366

GnomAD4 genome AF: 0.665 AC: 101130 AN: 152108 Hom.: 38361 Cov.: 32 AF XY: 0.669 AC XY: 49722 AN XY: 74348

African (AFR) AF: 0.294 AC: 12180 AN: 41462

American (AMR) AF: 0.806 AC: 12315 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 2566 AN: 3472

East Asian (EAS) AF: 0.393 AC: 2025 AN: 5150

South Asian (SAS) AF: 0.659 AC: 3181 AN: 4826

European-Finnish (FIN) AF: 0.868 AC: 9204 AN: 10600

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.841 AC: 57218 AN: 68006

Other (OTH) AF: 0.692 AC: 1458 AN: 2106

Alfa AF: 0.786 Hom.: 234236

Bravo AF: 0.644

TwinsUK AF: 0.847 AC: 3142

ALSPAC AF: 0.842 AC: 3244

ESP6500AA AF: 0.320 AC: 1356

ESP6500EA AF: 0.833 AC: 7030

ExAC AF: 0.737 AC: 89227

Asia WGS AF: 0.451 AC: 1572 AN: 3478

EpiCase AF: 0.846

EpiControl AF: 0.839

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)
-	-	3	not provided (3)
-	-	1	Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.085
Sift	Benign	0.030	D
Sift4G	Uncertain	0.012	D
Polyphen		0.82	P
Vest4		0.54
MPC		0.22
ClinPred		0.019	T
GERP RS		5.4
Varity_R		0.15
gMVP		0.43
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: rs7426114; hg19: chr2-152527572; COSMIC: COSV50868830;