chr2-151671094-C-T

Variant names:

• chr2-151671094-C-T
• rs34577613
• NM_001164507.2:c.4435G>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.4435G>A​(p.Val1479Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,613,714 control chromosomes in the GnomAD database, including 26,248 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1479V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.21 (4822 hom., cov: 32)
  • Exomes 𝑓: 0.14 (21426 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.308
• Publications: 27 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: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• 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=2.0170212E-4).
• BP6: Variant 2-151671094-C-T is Benign according to our data. Variant chr2-151671094-C-T is described in ClinVar as Benign. ClinVar VariationId is 129744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 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.4435G>A	p.Val1479Ile	missense	Exon 38 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.4435G>A	p.Val1479Ile	missense	Exon 38 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.4435G>A	p.Val1479Ile	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.4435G>A	p.Val1479Ile	missense	Exon 38 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.4435G>A	p.Val1479Ile	missense	Exon 38 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.4435G>A	p.Val1479Ile	missense	Exon 38 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31550 AN: 151988 Hom.: 4796 Cov.: 32

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.183 AC: 45602 AN: 249248 AF XY: 0.183

Gnomad AFR exome AF: 0.391

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.544

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.139 AC: 203548 AN: 1461608 Hom.: 21426 Cov.: 35 AF XY: 0.143 AC XY: 103634 AN XY: 727090

African (AFR) AF: 0.403 AC: 13503 AN: 33478

American (AMR) AF: 0.108 AC: 4832 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 4109 AN: 26136

East Asian (EAS) AF: 0.568 AC: 22556 AN: 39698

South Asian (SAS) AF: 0.281 AC: 24275 AN: 86256

European-Finnish (FIN) AF: 0.125 AC: 6681 AN: 53400

Middle Eastern (MID) AF: 0.149 AC: 857 AN: 5768

European-Non Finnish (NFE) AF: 0.105 AC: 116336 AN: 1111780

Other (OTH) AF: 0.172 AC: 10399 AN: 60370

GnomAD4 genome AF: 0.208 AC: 31635 AN: 152106 Hom.: 4822 Cov.: 32 AF XY: 0.209 AC XY: 15574 AN XY: 74374

African (AFR) AF: 0.383 AC: 15902 AN: 41470

American (AMR) AF: 0.126 AC: 1931 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 539 AN: 3472

East Asian (EAS) AF: 0.555 AC: 2859 AN: 5148

South Asian (SAS) AF: 0.286 AC: 1376 AN: 4816

European-Finnish (FIN) AF: 0.119 AC: 1259 AN: 10598

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.105 AC: 7165 AN: 68002

Other (OTH) AF: 0.205 AC: 432 AN: 2112

Alfa AF: 0.157 Hom.: 6386

Bravo AF: 0.216

TwinsUK AF: 0.0965 AC: 358

ALSPAC AF: 0.104 AC: 401

ESP6500AA AF: 0.357 AC: 1503

ESP6500EA AF: 0.109 AC: 920

ExAC AF: 0.190 AC: 22958

Asia WGS AF: 0.458 AC: 1589 AN: 3478

EpiCase AF: 0.0990

EpiControl AF: 0.105

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Nemaline myopathy 2 (4)
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	19
DANN	Benign	0.47
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.00020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.31
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.070
Sift	Benign	0.60	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.072
MPC		0.045
ClinPred		0.0024	T
GERP RS		4.3
Varity_R		0.031
gMVP		0.078
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: rs34577613; hg19: chr2-152527608; COSMIC: COSV50874383;