NM_001164507.2:c.8734T>C

Variant names:

• chr2-151640012-A-G
• rs6713162
• NM_001164507.2:c.8734T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):​c.8734T>C​(p.Ser2912Pro) variant causes a missense change. The variant allele was found at a frequency of 0.207 in 1,613,564 control chromosomes in the GnomAD database, including 49,168 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.31 (11054 hom., cov: 32)
  • Exomes 𝑓: 0.20 (38114 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.43
• Publications: 33 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, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=3.8599122E-5).
• BP6: Variant 2-151640012-A-G is Benign according to our data. Variant chr2-151640012-A-G is described in ClinVar as Benign. ClinVar VariationId is 129761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

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.8734T>C	p.Ser2912Pro	missense	Exon 62 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.8734T>C	p.Ser2912Pro	missense	Exon 62 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.8734T>C	p.Ser2912Pro	missense	Exon 62 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.8734T>C	p.Ser2912Pro	missense	Exon 62 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.8734T>C	p.Ser2912Pro	missense	Exon 62 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.8734T>C	p.Ser2912Pro	missense	Exon 62 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47545 AN: 151980 Hom.: 10994 Cov.: 32

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.607

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.289

GnomAD2 exomes AF: 0.243 AC: 60525 AN: 249014 AF XY: 0.240

Gnomad AFR exome AF: 0.644

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.594

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.196 AC: 286005 AN: 1461466 Hom.: 38114 Cov.: 33 AF XY: 0.198 AC XY: 144180 AN XY: 727032

African (AFR) AF: 0.648 AC: 21699 AN: 33474

American (AMR) AF: 0.145 AC: 6507 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 6487 AN: 26136

East Asian (EAS) AF: 0.622 AC: 24692 AN: 39694

South Asian (SAS) AF: 0.333 AC: 28694 AN: 86228

European-Finnish (FIN) AF: 0.142 AC: 7576 AN: 53390

Middle Eastern (MID) AF: 0.225 AC: 1296 AN: 5768

European-Non Finnish (NFE) AF: 0.157 AC: 174583 AN: 1111690

Other (OTH) AF: 0.240 AC: 14471 AN: 60362

GnomAD4 genome AF: 0.313 AC: 47659 AN: 152098 Hom.: 11054 Cov.: 32 AF XY: 0.310 AC XY: 23054 AN XY: 74360

African (AFR) AF: 0.630 AC: 26123 AN: 41456

American (AMR) AF: 0.189 AC: 2887 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 895 AN: 3466

East Asian (EAS) AF: 0.607 AC: 3139 AN: 5168

South Asian (SAS) AF: 0.335 AC: 1617 AN: 4824

European-Finnish (FIN) AF: 0.131 AC: 1387 AN: 10578

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10759 AN: 67996

Other (OTH) AF: 0.298 AC: 629 AN: 2114

Alfa AF: 0.218 Hom.: 18676

Bravo AF: 0.331

TwinsUK AF: 0.153 AC: 569

ALSPAC AF: 0.159 AC: 612

ESP6500AA AF: 0.598 AC: 2256

ESP6500EA AF: 0.165 AC: 1358

ExAC AF: 0.254 AC: 30680

Asia WGS AF: 0.546 AC: 1897 AN: 3478

EpiCase AF: 0.154

EpiControl AF: 0.160

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	0.031
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	22
DANN	Benign	0.59
DEOGEN2	Benign	0.0032	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.000039	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.8	N
PhyloP100		5.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	2.9	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.16
MPC		0.061
ClinPred		0.0072	T
GERP RS		5.5
Varity_R		0.20
gMVP		0.37
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: rs6713162; hg19: chr2-152496526; COSMIC: COSV50873704;