2-151619514-C-G

Variant names:

• chr2-151619514-C-G
• rs10172023
• NM_001164507.2:c.10809G>C

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.10809G>C​(p.Trp3603Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,613,274 control chromosomes in the GnomAD database, including 80,452 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. W3603R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.26 (5713 hom., cov: 32)
  • Exomes 𝑓: 0.32 (74739 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 3.22
• Publications: 21 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=0.0016649961).
• BP6: Variant 2-151619514-C-G is Benign according to our data. Variant chr2-151619514-C-G is described in ClinVar as Benign. ClinVar VariationId is 95102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 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.10809G>C	p.Trp3603Cys	missense	Exon 73 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.10809G>C	p.Trp3603Cys	missense	Exon 73 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.10809G>C	p.Trp3603Cys	missense	Exon 73 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.10809G>C	p.Trp3603Cys	missense	Exon 73 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.10809G>C	p.Trp3603Cys	missense	Exon 73 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.10080G>C	p.Trp3360Cys	missense	Exon 70 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39871 AN: 151940 Hom.: 5709 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.295

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.261

GnomAD2 exomes AF: 0.292 AC: 72637 AN: 248552 AF XY: 0.290

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.319

Gnomad ASJ exome AF: 0.236

Gnomad EAS exome AF: 0.263

Gnomad FIN exome AF: 0.341

Gnomad NFE exome AF: 0.326

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.315 AC: 460833 AN: 1461216 Hom.: 74739 Cov.: 40 AF XY: 0.312 AC XY: 226923 AN XY: 726800

African (AFR) AF: 0.138 AC: 4605 AN: 33470

American (AMR) AF: 0.313 AC: 13985 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 6063 AN: 26134

East Asian (EAS) AF: 0.258 AC: 10251 AN: 39686

South Asian (SAS) AF: 0.210 AC: 18107 AN: 86248

European-Finnish (FIN) AF: 0.338 AC: 18072 AN: 53394

Middle Eastern (MID) AF: 0.295 AC: 1702 AN: 5764

European-Non Finnish (NFE) AF: 0.333 AC: 370215 AN: 1111458

Other (OTH) AF: 0.295 AC: 17833 AN: 60352

GnomAD4 genome AF: 0.262 AC: 39883 AN: 152058 Hom.: 5713 Cov.: 32 AF XY: 0.263 AC XY: 19565 AN XY: 74308

African (AFR) AF: 0.139 AC: 5786 AN: 41512

American (AMR) AF: 0.265 AC: 4042 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 780 AN: 3464

East Asian (EAS) AF: 0.248 AC: 1276 AN: 5154

South Asian (SAS) AF: 0.217 AC: 1045 AN: 4824

European-Finnish (FIN) AF: 0.354 AC: 3737 AN: 10564

Middle Eastern (MID) AF: 0.297 AC: 86 AN: 290

European-Non Finnish (NFE) AF: 0.330 AC: 22450 AN: 67960

Other (OTH) AF: 0.258 AC: 546 AN: 2116

Alfa AF: 0.312 Hom.: 5653

Bravo AF: 0.253

TwinsUK AF: 0.340 AC: 1262

ALSPAC AF: 0.338 AC: 1301

ESP6500AA AF: 0.139 AC: 564

ESP6500EA AF: 0.331 AC: 2784

ExAC AF: 0.288 AC: 34864

Asia WGS AF: 0.233 AC: 811 AN: 3478

EpiCase AF: 0.313

EpiControl AF: 0.312

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	Nemaline myopathy 2 (5)
-	-	2	not provided (2)
-	-	1	Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Benign	0.065	N
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		3.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.58		Loss of catalytic residue at W3360 (P = 0.0794)
MPC		0.42
ClinPred		0.016	T
GERP RS		5.6
Varity_R		0.59
gMVP		0.62
Mutation Taster		=99/1	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: rs10172023; hg19: chr2-152476028; COSMIC: COSV51216946; COSMIC: COSV51216946;